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CEBPA mutations are particularly associated with cytogenetically normal AML (CN-AML). CEBPA is an intronless gene that is required for granulocyte formation in mice. N-terminal nonsense mutations result in a dominant negative C/EBP-alpha protein while C-terminal mutations reduce the DNA-binding potential of this transcription factor. CEBPA mutations are associated with a favorable prognosis, however, NPM1 and FLT3 mutations should also be assessed in CN-AML patients as concurrent mutations may have prognostic implications." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:1050", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "1050" }, "relation": "exactMatch" } ] }, "civic.gid:154": { "id": "civic.gid:154", "type": "MappableConcept", "name": "ACVR1", "extensions": [ { "name": "aliases", "value": [ "ACTRI", "ACVR1", "ACVR1A", "ACVRLK2", "ALK2", "FOP", "SKR1", "TSRI" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:90", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "90" }, "relation": "exactMatch" } ] }, "civic.gid:1728": { "id": "civic.gid:1728", "type": "MappableConcept", "name": "EPOR", "extensions": [ { "name": "aliases", "value": [ "EPO-R", "EPOR" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2057", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2057" }, "relation": "exactMatch" } ] }, "civic.gid:1771": { "id": "civic.gid:1771", "type": "MappableConcept", "name": "MECOM", "extensions": [ { "name": "aliases", "value": [ "AML1-EVI-1", "EVI1", "KMT8E", "MDS1", "MDS1-EVI1", "MECOM", "PRDM3", "RUSAT2" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2122", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2122" }, "relation": "exactMatch" } ] }, "civic.gid:18440": { "id": "civic.gid:18440", "type": "MappableConcept", "name": "FOXR2", "extensions": [ { "name": "aliases", "value": [ "FOXN6", "FOXR2" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:139628", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "139628" }, "relation": "exactMatch" } ] }, "civic.gid:1885": { "id": "civic.gid:1885", "type": "MappableConcept", "name": "FGFR1", "extensions": [ { "name": "aliases", "value": [ "BFGFR", "CD331", "CEK", "ECCL", "FGFBR", "FGFR-1", "FGFR1", "FLG", "FLT-2", "FLT2", "HBGFR", "HH2", "HRTFDS", "KAL2", "N-SAM", "OGD", "bFGF-R-1" ] }, { "name": "description", "value": "FGFR1 is a member of the Fibroblast Growth Factor family, comprising of 4 receptors and 18 Ligands. \nFGFR1 signalling downstream functions mainly via PI3K and MAPK pathways (Turner et. al.).\nSeveral ways of involvement of FGFR1 in cancer have been proposed: auto- and paracrine activation, amplification and overexpression (Marshall et. al, Weiss et. al., Cheng et. al.).\nEspecially amplification of FGFR1 in lung cancer is an emerging treatment target with clinical studies currently ongoing (e.g. NCT01004224). However, FGFR1 amplification does not always correlate with protein expression and predictive biomarkers still remain to be defined in clinic (von M\u00e4ssenhausen et. al.).\nMutation of FGFR1 seems to be less common, but has been described in glioblastoma, pilocytic astrocytomas and Ewing's sarcoma (Rand et. al., Jones et. al., Agelopoulos et. al.)." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2260", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2260" }, "relation": "exactMatch" } ] }, "civic.gid:19": { "id": "civic.gid:19", "type": "MappableConcept", "name": "EGFR", "extensions": [ { "name": "aliases", "value": [ "EGFR", "ERBB", "ERBB1", "ERRP", "HER1", "NISBD2", "NNCIS", "PIG61", "mENA" ] }, { "name": "description", "value": "EGFR is widely recognized for its importance in cancer. Amplification and mutations have been shown to be driving events in many cancer types. Its role in non-small cell lung cancer, glioblastoma and basal-like breast cancers has spurred many research and drug development efforts. Tyrosine kinase inhibitors have shown efficacy in EGFR amplfied tumors, most notably gefitinib and erlotinib. Mutations in EGFR have been shown to confer resistance to these drugs, particularly the variant T790M, which has been functionally characterized as a resistance marker for both of these drugs. The later generation TKI's have seen some success in treating these resistant cases, and targeted sequencing of the EGFR locus has become a common practice in treatment of non-small cell lung cancer. Overproduction of ligands is another possible mechanism of activation of EGFR. ERBB ligands include EGF, TGF-a, AREG, EPG, BTC, HB-EGF, EPR and NRG1-4 (for detailed information please refer to the respective ligand section)." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:1956", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "1956" }, "relation": "exactMatch" } ] }, "civic.gid:1955": { "id": "civic.gid:1955", "type": "MappableConcept", "name": "FOS", "extensions": [ { "name": "aliases", "value": [ "AP-1", "C-FOS", "FOS", "p55" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2353", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2353" }, "relation": "exactMatch" } ] }, "civic.gid:1956": { "id": "civic.gid:1956", "type": "MappableConcept", "name": "FOSB", "extensions": [ { "name": "aliases", "value": [ "AP-1", "FOSB", "G0S3", "GOS3", "GOSB" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2354", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2354" }, "relation": "exactMatch" } ] }, "civic.gid:20": { "id": "civic.gid:20", "type": "MappableConcept", "name": "ERBB2", "extensions": [ { "name": "aliases", "value": [ "CD340", "ERBB2", "HER-2", "HER-2/neu", "HER2", "MLN 19", "MLN-19", "NEU", "NGL", "TKR1", "VSCN2", "c-ERB-2", "c-ERB2", "p185(erbB2)" ] }, { "name": "description", "value": "ERBB2, commonly referred to as HER2, is amplified and/or overexpressed in 20-30% of invasive breast carcinomas. HER2-positive breast cancer is treated in a separate manner from other subtypes of breast cancer and commonly presents as more aggressive disease. Metastatic HER2-positive breast cancer is now commonly treated with HER2-targeted therapy. Apart from being amplified/overexpressed, ERBB2 activating mutations have been shown to have clinical importance in HER2-negative breast cancer. These mutations have shown sensitivity to the tyrosine kinase inhibitor neratinib, and highlight the importance of clinical sequencing efforts in treating breast cancer." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2064", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2064" }, "relation": "exactMatch" } ] }, "civic.gid:23": { "id": "civic.gid:23", "type": "MappableConcept", "name": "FGFR3", "extensions": [ { "name": "aliases", "value": [ "ACH", "CD333", "CEK2", "FGFR3", "HSFGFR3EX", "JTK4" ] }, { "name": "description", "value": "The FGFR proteins are involved in a wide array of pathways known to play a signficant role in cancer. Activation of these receptors can lead to activation of the RAS-MAPK pathway and the PI3K-AKT pathway, among others. The mechanisms by which FGFR can be misregulated vary between cancers. Amplification of the receptors has been observed in lung and breast cancers, coding mutations and deletions have been seen in many cancers, and more recently, FGFR fusions that lead to pathway actiation have been demonstrated to have oncogenic potential across multiple cancer types. The targeted therapeutics ponatinib, dovitinib and pazopanib have seen success in treating over-active FGFR signalling, prompting use of diagnostic sequencing targeting the FGFR genes, especially in lung cancer patients." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2261", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2261" }, "relation": "exactMatch" } ] }, "civic.gid:24": { "id": "civic.gid:24", "type": "MappableConcept", "name": "FLT3", "extensions": [ { "name": "aliases", "value": [ "CD135", "FLK-2", "FLK2", "FLT3", "STK1" ] }, { "name": "description", "value": "FLT3 is an important cytokine receptor involved in normal hematopoiesis. Mutations in this gene are common in acute myeloid leukemia (AML) and screening for mutations in this gene has been recommended by the World Health Organization in patients with AML, particularly in cases of cytogenetically normal AML (CN-AML). FLT3 mutations commonly co-occur with mutations such as NPM1 that are associated with CN-AML and likely modulate prognostic impact. While FLT3-ITD mutations have been associated with poorer prognosis in AML, the prognostic impact of FLT3-TKD mutations are still up for debate." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:2322", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "2322" }, "relation": "exactMatch" } ] }, "civic.gid:2537": { "id": "civic.gid:2537", "type": "MappableConcept", "name": "H3-3A", "extensions": [ { "name": "aliases", "value": [ "BRYLIB1", "H3-3A", "H3.3A", "H3F3", "H3F3A" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:3020", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "3020" }, "relation": "exactMatch" } ] }, "civic.gid:26": { "id": "civic.gid:26", "type": "MappableConcept", "name": "IDH1", "extensions": [ { "name": "aliases", "value": [ "HEL-216", "HEL-S-26", "IDCD", "IDH", "IDH1", "IDP", "IDPC", "PICD" ] }, { "name": "description", "value": "IDH1 mutations have been observed in a number of cancer types, including sarcomas, hematologic malignancies, colon cancer and brain cancer. Mutations in the two isocitrate dehydrogenase enzymes involved in cytoplasmic (IDH1) and mitochondrial (IDH2) conversion of alpha-ketoglutarate to D-2-hydroxyglutarate have been described as mutually exclusive in many of these cancer types. The most frequent mutations involve R132 (IDH1) and R172 (IDH2) involve the active site and result in neomorphic enzyme activity. The implications of mutations in this gene vary greatly by cancer type. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 mutations have been associated with worse outcome, shorter overall survival, and normal karyotype. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Unlike the association with cytogenetically normal AML, in glioblastoma, IDH1 mutations have been associated with specific cytogenetic abnormalities, 1p and 19q deletions." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:3417", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "3417" }, "relation": "exactMatch" } ] }, "civic.gid:2747": { "id": "civic.gid:2747", "type": "MappableConcept", "name": "HRAS", "extensions": [ { "name": "aliases", "value": [ "C-BAS/HAS", "C-H-RAS", "C-HA-RAS1", "CTLO", "H-RASIDX", "HAMSV", "HRAS", "HRAS1", "RASH1", "p21ras" ] }, { "name": "description", "value": "HRAS is a member of the small GTPase family that upon activation by receptor tyrosine kinases stimulates downstream pathways including RAF-MEK-ERK and PI3K-AKT. In cancer, recurrent gain-of-function mutations at positions G12, G13, and Q61 result in an accumulation of GTP-bound HRAS, constitutive downstream signaling, and transformation. In TCGA, HRAS mutations were found more frequently in head and neck squamous cell carcinoma, bladder urothelial carcinoma, thyroid carcinoma, thymoma, skin cutaneous carcinoma, and pheochromocytoma/paraganglioma. Although development of HRAS inhibitors has not been possible, targeting the enzyme essential for farnesylating HRAS has recently shown benefit in HRAS driven cancers. The farnesyltransferase inhibitor (FTi) tipifarnib has been shown to cause HRAS mislocalization, decrease downstream signaling, and selectively impair proliferation, survival, and transformation of HRAS-mutant cells. Tipifarnib is in clinical development for HRAS-mutant cancers." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:3265", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "3265" }, "relation": "exactMatch" } ] }, "civic.gid:29": { "id": "civic.gid:29", "type": "MappableConcept", "name": "KIT", "extensions": [ { "name": "aliases", "value": [ "C-Kit", "CD117", "KIT", "MASTC", "PBT", "SCFR" ] }, { "name": "description", "value": "c-KIT activation has been shown to have oncogenic activity in gastrointestinal stromal tumors (GISTs), melanomas, lung cancer, and other tumor types. The targeted therapeutics nilotinib and sunitinib have shown efficacy in treating KIT overactive patients, and are in late-stage trials in melanoma and GIST. KIT overactivity can be the result of many genomic events from genomic amplification to overexpression to missense mutations. Missense mutations have been shown to be key players in mediating clinical response and acquired resistance in patients being treated with these targeted therapeutics." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:3815", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "3815" }, "relation": "exactMatch" } ] }, "civic.gid:3": { "id": "civic.gid:3", "type": "MappableConcept", "name": "ARAF", "extensions": [ { "name": "aliases", "value": [ "A-RAF", "ARAF", "ARAF1", "PKS2", "RAFA1" ] }, { "name": "description", "value": "ARAF has recently become increasingly considered for its oncogenic potential. Its potential as a target for informing clinical action was demonstrated by a single case of advanced lung adenocarcinoma harboring an S214C mutation that, when treated with sorafenib, acheived near-complete clinical remission. This finding has brought new focus on ARAF as a marker that should be assayed for in cancer treatment." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:369", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "369" }, "relation": "exactMatch" } ] }, "civic.gid:31": { "id": "civic.gid:31", "type": "MappableConcept", "name": "MAP2K1", "extensions": [ { "name": "aliases", "value": [ "CFC3", "MAP2K1", "MAPKK1", "MEK1", "MEL", "MKK1", "PRKMK1" ] }, { "name": "description", "value": "MAP2K1 is a dual-specificity kinase known for it's involvement in the ERK pathway by activation of ERK1 and ERK2. MAP2K1 activating mutations have been observed in a number of cancers including ovarian, melanoma and lung. These activating mutations are generally found in the N-terminal negative regulatory region or the ATP-binding region of the N-terminal lobe. Inhibitors of MEK genes have been shown to inhibit tumor growth in these cases." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:5604", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "5604" }, "relation": "exactMatch" } ] }, "civic.gid:35": { "id": "civic.gid:35", "type": "MappableConcept", "name": "NPM1", "extensions": [ { "name": "aliases", "value": [ "B23", "NPM", "NPM1" ] }, { "name": "description", "value": "AML with mutated NPM1 is a provisional entity in the WHO classification of AML and is recommended to be tested in patients with cytogenetically normal AML (CN-AML). FLT3 mutations should be evaluated concurrently as they have prognostic consequences. NPM1 mutations are concentrated in exon 12, most frequently W288fs which results in cytoplasmic sequestration of the protein. Exon 12 NPM1 mutations in the absence of FLT3-ITD are associated with good prognostic outcomes. Mice expressing the Npm1-W288fs mutation develop myeloproliferative neoplasms but not overt leukemia, indicating it may require additional mutations to promote leukemic development." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:4869", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "4869" }, "relation": "exactMatch" } ] }, "civic.gid:3564": { "id": "civic.gid:3564", "type": "MappableConcept", "name": "MN1", "extensions": [ { "name": "aliases", "value": [ "CEBALID", "MGCR", "MGCR1", "MGCR1-PEN", "MN1", "dJ353E16.2" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:4330", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "4330" }, "relation": "exactMatch" } ] }, "civic.gid:3730": { "id": "civic.gid:3730", "type": "MappableConcept", "name": "MYB", "extensions": [ { "name": "aliases", "value": [ "Cmyb", "MYB", "c-myb", "c-myb_CDS", "efg" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:4602", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "4602" }, "relation": "exactMatch" } ] }, "civic.gid:3731": { "id": "civic.gid:3731", "type": "MappableConcept", "name": "MYBL1", "extensions": [ { "name": "aliases", "value": [ "A-MYB", "AMYB", "MYBL1" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:4603", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "4603" }, "relation": "exactMatch" } ] }, "civic.gid:3777": { "id": "civic.gid:3777", "type": "MappableConcept", "name": "MYOD1", "extensions": [ { "name": "aliases", "value": [ "CMYO17", "CMYP17", "MYF3", "MYOD", "MYOD1", "MYODRIF", "PUM", "bHLHc1" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:4654", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "4654" }, "relation": "exactMatch" } ] }, "civic.gid:4111": { "id": "civic.gid:4111", "type": "MappableConcept", "name": "PAX5", "extensions": [ { "name": "aliases", "value": [ "ALL3", "BSAP", "PAX-5", "PAX5" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:5079", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "5079" }, "relation": "exactMatch" } ] }, "civic.gid:42": { "id": "civic.gid:42", "type": "MappableConcept", "name": "RET", "extensions": [ { "name": "aliases", "value": [ "CDHF12", "CDHR16", "HSCR1", "MEN2A", "MEN2B", "MTC1", "PTC", "RET", "RET-ELE1" ] }, { "name": "description", "value": "RET mutations and the RET fusion RET-PTC lead to activation of this tyrosine kinase receptor and are associated with thyroid cancers. RET point mutations are the most common mutations identified in medullary thyroid cancer (MTC) with germline and somatic mutations in RET associated with hereditary and sporadic forms, respectively. The most common somatic form mutation is M918T (exon 16) and a variety of other mutations effecting exons 10, 11 and 15 have been described. The prognostic significance of these mutations have been hotly debated in the field, however, data suggests that some RET mutation may confer drug resistance. Highly selective and well-tolerated RET inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been FDA approved recently for the treatment of RET fusion-positive non-small-cell lung cancer, RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:5979", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "5979" }, "relation": "exactMatch" } ] }, "civic.gid:4767": { "id": "civic.gid:4767", "type": "MappableConcept", "name": "RAF1", "extensions": [ { "name": "aliases", "value": [ "CMD1NN", "CRAF", "NS5", "RAF1", "Raf-1", "c-Raf" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:5894", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "5894" }, "relation": "exactMatch" } ] }, "civic.gid:5": { "id": "civic.gid:5", "type": "MappableConcept", "name": "BRAF", "extensions": [ { "name": "aliases", "value": [ "B-RAF1", "B-raf", "BRAF", "BRAF-1", "BRAF1", "NS7", "RAFB1" ] }, { "name": "description", "value": "BRAF mutations are found to be recurrent in many cancer types. Of these, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent. V600E has been determined to be an activating mutation, and cells that harbor it, along with other V600 mutations are sensitive to the BRAF inhibitor dabrafenib. It is also common to use MEK inhibition as a substitute for BRAF inhibitors, and the MEK inhibitor trametinib has seen some success in BRAF mutant melanomas. BRAF mutations have also been correlated with poor prognosis in many cancer types, although there is at least one study that questions this conclusion in papillary thyroid cancer.\n\nOncogenic BRAF mutations are divided into three categories that determine their sensitivity to inhibitors.\nClass 1 BRAF mutations (V600) are RAS-independent, signal as monomers and are sensitive to current RAF monomer inhibitors.\nClass 2 BRAF mutations (K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, and fusions) are RAS-independent, signaling as constitutive dimers and are resistant to vemurafenib. Such mutants may be sensitive to novel RAF dimer inhibitors or MEK inhibitors.\nClass 3 BRAF mutations (D287H, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, and G596R) with low or absent kinase activity are RAS-dependent and they activate ERK by increasing their binding to activated RAS and wild-type CRAF. Class 3 BRAF mutations coexist with mutations in RAS or NF1 in melanoma may be treated with MEK inhibitors. In epithelial tumors such as CRC or NSCLC may be effectively treated with combinations that include inhibitors of receptor tyrosine kinase." } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:673", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "673" }, "relation": "exactMatch" } ] }, "civic.gid:5356": { "id": "civic.gid:5356", "type": "MappableConcept", "name": "SMARCB1", "extensions": [ { "name": "aliases", "value": [ "BAF47", "CSS3", "INI-1", "INI1", "MRD15", "PPP1R144", "RDT", "RTPS1", "SMARCB1", "SNF5", "SNF5L1", "SWNTS1", "Sfh1p", "Snr1", "hSNFS" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:6598", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "6598" }, "relation": "exactMatch" } ] }, "civic.gid:6614": { "id": "civic.gid:6614", "type": "MappableConcept", "name": "H3C2", "extensions": [ { "name": "aliases", "value": [ "H3/l", "H3C2", "H3FL", "HIST1H3B" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:8358", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "8358" }, "relation": "exactMatch" } ] }, "civic.gid:67": { "id": "civic.gid:67", "type": "MappableConcept", "name": "AR", "extensions": [ { "name": "aliases", "value": [ "AIS", "AR", "AR8", "DHTR", "HPCX3", "HUMARA", "HYSP1", "KD", "NR3C4", "SBMA", "SMAX1", "TFM" ] } ], "conceptType": "Gene", "mappings": [ { "coding": { "id": "ncbigene:367", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "367" }, "relation": "exactMatch" } ] } }, "molecularProfile": { "civic.mpid:113": { "id": "civic.mpid:113", "type": "CategoricalVariant", "name": "RET M918T", "description": "RET M918T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). 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"isDiagnosticInclusionCriterionFor", "object": "#/conditionSet/civic.conditionSet:KjuVJ4KNCLm4egy_jLrmzeXDZb3IV7If", "geneContextQualifier": "#/feature/civic.gid:3730", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC" }, "civic.proposition:yqxCLfkXteFOYvE-1GtJ9wXWc1HCBEg0": { "id": "civic.proposition:yqxCLfkXteFOYvE-1GtJ9wXWc1HCBEg0", "type": "VariantOncogenicityProposition", "subject": "#/molecularProfile/civic.mpid:624", "predicate": "isOncogenicFor", "object": "#/disease/civic.did:216", "geneContextQualifier": "#/feature/civic.gid:23", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC" }, "civic.proposition:yvWibePmbsIs6FfPAVx_MwzV3k3mi9EQ": { "id": "civic.proposition:yvWibePmbsIs6FfPAVx_MwzV3k3mi9EQ", "type": "VariantDiagnosticProposition", "subject": "#/molecularProfile/civic.mpid:2566", "predicate": "isDiagnosticInclusionCriterionFor", "object": "#/conditionSet/civic.conditionSet:HXw1Gj-oihN9no945VldlZRE75SPjeqy", "geneContextQualifier": "#/feature/civic.gid:4111", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC" }, "civic.proposition:zV75hr3o6OVknaKJG4D8hsqdycyKaDpQ": { "id": "civic.proposition:zV75hr3o6OVknaKJG4D8hsqdycyKaDpQ", "type": "VariantTherapeuticResponseProposition", "subject": "#/molecularProfile/civic.mpid:433", "predicate": "predictsSensitivityTo", "object": "#/therapy/civic.tid:641", "geneContextQualifier": "#/feature/civic.gid:24", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC", "conditionQualifier": "#/disease/civic.did:3" } }, "evidence": { "civic.eid:103": { "id": "civic.eid:103", "type": "Statement", "description": "V600E is associated with adverse pathological features of colorectal cancer. This can be concluded as a marker of poor prognosis.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:110" ], "proposition": "#/proposition/civic.proposition:sXFJwmFRv74A8_wLpTiNttPaZo_dDR52", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:108": { "id": "civic.eid:108", "type": "Statement", "description": "In this publication, the role of NPM1 mutations in defining a distinct subset of acute myeloid leukemia (AML) was investigated. Among 1,485 adult AML patients enrolled in the multicenter AML96 protocol, fragment analysis and Sanger sequencing identified NPM1 insertion mutations in 27.5% of cases, most commonly within the terminal coding exon (historically referred to as exon 12). These mutations resulted in cytoplasmic mislocalization of the NPM1 protein, a feature confirmed by confocal microscopy.\nThe study demonstrated that NPM1 mutations occur most frequently in AML patients with a normal karyotype and are strongly associated with characteristic clinicopathologic features, including higher leukocyte and blast counts. NPM1 mutations were found in conjunction with FLT3-ITDs (internal tandem duplications) in 40.2% (164/408) of patients. Analysis of the mutant/wild type ratio for patients harboring both NPM1 mutations and FLT3-ITDs indicated that NPM1 mutations were present in a higher percent of blasts, suggesting they are a primary event in AML patients, preceding the acquisition of FLT3-ITD mutations.\nFrom a clinical perspective, the presence of an NPM1 mutation was shown to confer a distinct biological entity with prognostic implications. Patients with NPM1-mutated AML, in the absence of FLT3-ITDs, had significantly improved overall survival, disease-free survival, and lower relapse incidence compared with other AML subgroups. Multivariate analysis confirmed that NPM1 mutations alone represent an independent favorable prognostic factor.\nThis study identified AML with mutated NPM1 as a common, biologically distinct entity, marked by elevated bone marrow blasts, increased white blood cell and platelet counts, a higher incidence in females, association with a normal karyotype, frequent co-occurrence of FLT3 mutations, and favorable outcomes in cases lacking FLT3 mutations.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:113" ], "proposition": "#/proposition/civic.proposition:FieV3ZZI2vPPWcQmyJlvN8LRCQQ-4qWW", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:10800": { "id": "civic.eid:10800", "type": "Statement", "description": "The authors generated genome-wide DNA methylation profiles of 323 tumors with an institutional diagnosis of \u2018primitive neuroectodermal tumors of the central nervous system (CNS-PNETs)\u2019, which are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Four novel methylation profiles were identified. One of those profiles was exhibited by 10/323 (3 %) cases, and all these tumors were found to have a duplicated region in exon 15 of BCOR [BCOR internal tandem duplication (ITD)] by DNA/RNA sequencing, identical to that of the BCOR ITD in other tumor types including clear cell sarcomas of the kidney, undifferentiated round cell sarcomas in infants, and primitive myxoid mesenchymal tumour of infancy. The authors compared DNA methylation pattern of the BCOR-ITD positive cases with an in-house collection of > 10,000 methylation profiles from a broad variety of pediatric and adult CNS tumors. Additional tumors with variety of histologies showed the same methylation profile as BCOR-ITD positive cases, and were also found to have BCOR-ITD. The authors proposed that BCOR-ITD defines a specific molecular subtype of CNS tumors.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3559" ], "proposition": "#/proposition/civic.proposition:laytJ2G_KAnsOApe-nWLjmhxhx-6e-pe", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:10801": { "id": "civic.eid:10801", "type": "Statement", "description": "BCOR internal tandem duplications (ITDs) were found frequently in cases of clear cell sarcoma of kidney (CCSK), a rare pediatric renal cancer. The study initially evaluated 3 CCSK samples by whole exome sequencing and whole transcriptome sequencing. All 3 samples demonstrated BCOR ITD by RNA sequencing. This was further validated by targeted DNA sequencing of a validation institutional cohort of 11 primary and 2 matched metastatic CCSK cases, and an additional external cohort of 13 CCSK samples. Overall, BCOR ITDs were found in 85% (23/27 cases). No BCOR ITDs were found in neither matched normal kidney/blood, nor other childhood renal cancers. Upregulation of mutant BCOR transcripts and protein expression by immunoblotting and immunohistochemistry was shown.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4397" ], "proposition": "#/proposition/civic.proposition:ngk0lKL_WKuwTV3NbRbgBiGEuoh1sWli", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:10887": { "id": "civic.eid:10887", "type": "Statement", "description": "10 cases of high-grade neuroepithelial tumor (HGNET) with BCOR exon 15 ITD were studied. In addition, 25 previously reported and published patients were included in survival analyses. These tumors are newly proposed to belong to a separate entity with a distinct methylation profile and a characteristic genetic alteration. The authors further describe their clinical, pathologic, radiographic, and genetic features. Shared histologic characteristics included predominantly solid growth, glioma\u2010like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. Immunohistochemistry testing showed absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. In 6 of 10 cases, BCOR ex15 ITD was the only pathogenic alteration seen, while other cases showed additional genetic abnormalities including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. The authors conclude that their findings further support inclusion of HG NET with BCOR ex15 ITD as a distinct CNS tumor entity.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4411" ], "proposition": "#/proposition/civic.proposition:OGVPQeSJXDNHxxLQB6ST4m00P969TG9g", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11160": { "id": "civic.eid:11160", "type": "Statement", "description": "In this open-label phase II study, 20 patients with systemic mastocytosis (SM) were enrolled between 2003 and 2005 and treated with imatinib mesylate. Thirteen of the 20 patients were positive for the KIT D816V mutation. Among these patients, no objective clinical responses were observed. Two patients with the KIT D816V mutation reported symptomatic improvement, including improvement in fatigue in one patient and diarrhea in another; however, no measurable changes in bone marrow mast cell involvement or consistent reductions in serum tryptase levels were documented in this subgroup.\nOverall, only one patient in the study achieved a complete response, and this patient was negative for the KIT D816V mutation. The remaining patients, including those with KIT D816V mutation, showed no significant clinical benefit from imatinib therapy.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4567" ], "proposition": "#/proposition/civic.proposition:uGUz3ucb6Qr0cT2gl_Rg3zhxSaZxlQiD", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:1122": { "id": "civic.eid:1122", "type": "Statement", "description": "HERA was a Phase III trial assessing application of trastuzumab in an extended adjuvant setting. Patients were HER2 positive with completely excised invasive BC, node positive or negative, and having undergone prior adjuvant or neo-adjuvant chemotherapy. In the 3 arm study patients were given trastuzumab courses of 1 year, 2 years, or untreated. At the first planned interim analysis, trastuzumab treatment for one year was compared with observation alone. A significant difference in disease-free survival was seen with 220 DFS events out of 1693 in the observation arm versus 127 DFS events out of 1694 in the 1 year trastuzumab arm. 1 year adjuvant trastuzumab is currently the standard of care.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:777" ], "proposition": "#/proposition/civic.proposition:FonbMwrb-ED595aPspkqm9KmG4hPUrLR", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:11423": { "id": "civic.eid:11423", "type": "Statement", "description": "High BCOR expression which was associated with an internal tandem duplication (ITD) of 89 to 144 bp in exon 16 of the BCOR gene was identified in 20 of 20 (100%) of cases of clear cell sarcoma of the kidney, but not in any of the other 193 pediatric renal tumors tested. This suggested that BCOR ITD may be useful in the diagnosis of clear cell sarcoma of the kidney.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4711" ], "proposition": "#/proposition/civic.proposition:tRhMvcZfPGf0hkRHp154Da-8eujCQtd9", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11424": { "id": "civic.eid:11424", "type": "Statement", "description": "Whole transcriptome sequencing on tumors from 8 patients with clear cell sarcoma of the kidney identified BCOR ITD and overexpression of BCOR in all samples. The BCOR ITD was confirmed on tumor DNA. All samples showed numerous deleterious SNVs and InDels, but none were common among all samples. BCOR ITD was the only common, recurrent alteration.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4712" ], "proposition": "#/proposition/civic.proposition:Zfjb6tIet_EEcOh2ysdPZa6Cye4HgOAc", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11519": { "id": "civic.eid:11519", "type": "Statement", "description": "RNA-seq transcriptome analysis in a discovery cohort of 170 B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases negative for the common classifying cytogenetic aberrations identified several well-defined hierarchical expression clusters. Four clusters corresponded to known oncogenic subtypes, namely ZNF384, ERG/DUX4, BCR::ABL1-like, and KMT2A/MLL-rearranged. An additional cluster comprised 14 cases (8.2%), which lacked any fusion gene. Mutational analysis of RNA-seq data revealed the presence of a unique PAX5 mutation, c.239C>G, p.Pro80Arg (p.P80R), in all cases. In an additional cohort of 419 unselected BCP-ALL cases, PAX5 P80R was identified in 16 (5.3%). The authors conclude that the PAX5 P80R variant, with its distinct transcriptional signature, defines a subtype of BCP-ALL.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4774" ], "proposition": "#/proposition/civic.proposition:JloRy5yEeKh1NK29tODJbp3UeULuLED6", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11527": { "id": "civic.eid:11527", "type": "Statement", "description": "In the 2016 study by Sturm et al., the authors performed comprehensive molecular profiling, including DNA methylation arrays, transcriptomics, and genome-wide sequencing, on 323 institutionally diagnosed central nervous system primitive neuroectodermal tumors (CNS-PNETs). Through unsupervised clustering of DNA methylation profiles, they identified a novel molecular entity termed CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), comprising 44 out of 323 cases (14%), later expanded to 46 cases through comparison with a larger reference cohort. This entity was characterized by embryonal small cell histology, frequent neuropil and ganglion cell differentiation, and expression of OLIG2 and synaptophysin. Whole-genome sequencing revealed inter- and intra-chromosomal rearrangements involving upstream regions of FOXR2 that retained its full coding sequence in 6 of 8 sequenced cases. These included repositioning of FOXR2 adjacent to active genomic loci (e.g., JMJD1C, LOC550643, JPX), recurrent upstream deletions (notably, 4 of 46 cases had deletions reaching ~500 kb upstream of FOXR2, potentially repositioning it near MAGED2), and a mitochondrial DNA insertion into USP51 that formed a novel promoter driving FOXR2 expression. In this cohort, FOXR2 was highly expressed in CNS NB-FOXR2 tumors, but not expressed in other CNS tumor types or normal brain tissue, suggesting promoter switching or enhancer hijacking as mechanisms of oncogenic activation. Additionally, copy number analysis showed gain of chromosome arm 1q in 43 of 44 cases (98%), loss of 16q in 21 of 42 cases (50%), and gain of chromosome 8 in 14 of 44 cases (32%). One exceptional case lacked FOXR2 activation but had MYC amplification, indicating an alternative oncogenic driver. This study established CNS NB-FOXR2 as a distinct molecular entity, refining the classification of CNS embryonal tumors.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3559" ], "proposition": "#/proposition/civic.proposition:aW1DTrk0v0DOnN9-YfoKlGSuQu4Z3fi9", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11528": { "id": "civic.eid:11528", "type": "Statement", "description": "DNA methylation profiling of 84 tumors initially diagnosed as CNS-PNET identified CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2) as a distinct molecular subgroup, presented in 24% (20/84) of cases. RNA sequencing revealed FOXR2 gene fusion transcripts in all 14 CNS NB-FOXR2 tumors analyzed, including intergenic duplication involving the FOXR2 coding sequence on chromosome Xp11.21 and rearrangements with LINC00486 (2p22), TM7SF3 (12p11.23), and FRMD4A (10p11.3). All 14 CNS NB-FOXR2 tumors showed high level of FOXR2 gene expression. Copy number analysis showed frequent 1q gain (100%), 16q loss (70%), and 17q gain (62%), with no recurrent point mutations or oncogene amplifications. Transcriptomic profiling identified SOX10 and ANKRD55 as highly expressed genes that appear to be specific to CNS NB-FOXR2.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4781" ], "proposition": "#/proposition/civic.proposition:aW1DTrk0v0DOnN9-YfoKlGSuQu4Z3fi9", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11581": { "id": "civic.eid:11581", "type": "Statement", "description": "Six cases of CNS high-grade neuroepithelial tumor (HGNET) with BCOR exon 15 internal tandem duplication (ITD) were studied. The authors analyzed their clinical, pathologic and molecular characteristic and compared them with Clear Cell Sarcoma of Kidney (CCSK) and soft tissue sarcoma with the same genetic abnormality (BCOR ex15 ITD). Cases of CNS HGNET with BCOR ex15 ITD were histologically characterized by glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis. Immunohistochemically, they showed diffuse staining of Olig2, and focal staining of GFAP, S-100 protein and synaptophysin. Clinically, histologically and immunohistochemically CNS HG NETs with BCOR ex15 ITD were distinct from CCSK and soft tissue sarcomas with BCOR ex15 ITD, supporting that these should be considered a unique type of CNS tumor.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4805" ], "proposition": "#/proposition/civic.proposition:FIAoj1eodvLDAazs-n1gyZdTVC4OWxOH", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11582": { "id": "civic.eid:11582", "type": "Statement", "description": "This study assessed MYOD1 exon 1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcoma. 5 sclerosing (2 pediatric and 3 adults) and 11 spindle cell rhabdomyosarcomas (3 pediatric and 8 adults) were subject to targeted PCR and sanger sequencing of MYOD1 exon 1 hotspot mutation and PIK3CA exon 9 and exon 20 mutations. FISH analysis for MDM2 and CDK4 amplification was also performed. A total of 9 RMS (4 pediatric and 5 adult type) cases were positive for MYOD1 p.L122R hotspot mutation which included all 5 sclerosing RMS and 4/11 spindle cell RMS (2/3 pediatric and 2/8 adult). 3/9 MYOD1-mutant RMS showed additional PIK3CA mutation in exon 9 while no kinase domain (exon 20) mutations were identified. None of the cases harbored MDM2 gene amplification. The recurrent MYOD1 mutation supports spindle cell and sclerosing RMS being a single pathogenic entity.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4806" ], "proposition": "#/proposition/civic.proposition:LAZqsEacVYgqNrYeiTgODWJdFmiHxuGk", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11585": { "id": "civic.eid:11585", "type": "Statement", "description": "This study assessed the clinicopathologic and molecular features of 13 spindle cell (SRMS) and 7 spindle cell/sclerosing rhabdomyosarcomas (ScRMS) arising in the head and neck region. Age ranged from 2 months to 57 years. All ScRMS (n=7) and 8/13 SRMS showed MYOD1 p.L122R mutation. A PIK3CA mutation was seen in 7/13 SRMS and 4/7 ScRMS, 8 of which had concomitant MYOD1 mutation. MYOD1 p.L122R mutation is a recurrent event and supports the diagnosis of SRMS and ScRMS.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4799" ], "proposition": "#/proposition/civic.proposition:Y_CFlEspqpK7dvL8l0VPNl-A8f1LJP6K", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11588": { "id": "civic.eid:11588", "type": "Statement", "description": "In this study, FISH, targeted DNA, and whole transcriptome sequencing were used to define a better molecular classification of sclerosing and spindle cell rhabdomyosarcoma. 11 of 26 were congenital/infantile type diagnosed at birth or within one year of age, 10 of which harbored recurrent fusions involving VGLL2 or NCOA2 genes. The remaining 15 cases were diagnosed in older patients (2-17 years old); 10 showed MYOD1 p.L122R mutation, 4 of which showed an additional concomitant PIK3CA mutation (p.E542V, p.E545K, p.Q546R, or p.G1049R). Cases with both PIK3CA and MYOD1 mutations were uniformly characterized by a sclerosing histology. MYOD1 mutation was homozygous in 8 cases. This supports MYOD1 p.L122R as diagnostic for spindle cell / sclerosing rhabdomyosarcoma.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4800" ], "proposition": "#/proposition/civic.proposition:LH1nIbSrvISBSnx3Gdq0Pf9NP_4_c6Uv", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11596": { "id": "civic.eid:11596", "type": "Statement", "description": "Whole-genome DNA and RNA sequencing of 5 osteoblastomas and 1 osteoid osteoma identified FOS rearrangements in 5 tumors (4 osteoblastomas and 1 osteoid osteoma) and a FOSB rearrangement in 1 osteoblastomas. All 5 FOS rearrangements retained the 5' end of FOS (including the dominant transactivation domain and the bZIP domain), which was fused to various 3' partners (including KIAA1199, MYO1B, ANKH, and intergenic regions) contributing an in-frame stop codon prior to the proteasome degradation motif of FOS. To ascertain how common FOS rearrangements may be, break-apart FISH in-situ hybridization Immunohistochemistry (IHC) was used on an additional 55 cases. 87% (48 of 55) were positive for FOS rearrangement, and FOS IHC was high in nearly all the FOS rearranged samples tested. The authors conclude that these benign human bone tumors may be defined by genetic rearrangements of FOS (or FOSB in a smaller subset). Identification of the FOS or FOSB rearrangement may help differentiate these benign tumors from the more aggressive osteoblastic osteosarcoma.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4814" ], "proposition": "#/proposition/civic.proposition:TBlYlw_LmoPznrejvzW3Y7iUOrsRnATU", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11774": { "id": "civic.eid:11774", "type": "Statement", "description": "Copy-number analysis was performed on 44 diffuse pediatric low-grade gliomas (PLGGs) to identify recurrent alterations. The most significant event, focal 8q13.1 gain, was observed in 28% (5/18) of diffuse astrocytoma grade IIs (DA2), resulting in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A recurrent deletion-truncation breakpoint between exons 10 and 11 of MYB on 6q23.3 was identified in two of four angiocentric gliomas (AGs). This study did not mention the partner genes involved in the MYB rearrangements in the two AGs. The results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4907" ], "proposition": "#/proposition/civic.proposition:24GDqOKeG0dNuxm9h5glUt_8ojmy0AlN", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:11775": { "id": "civic.eid:11775", "type": "Statement", "description": "A research study performed in 2010 involved 57 pediatric low-grade gliomas (LGGs) and a comparison group of 59 pediatric high-grade gliomas (HGGs). Among the LGG group, there were 34 cases of pilocytic astrocytomas (PAs) and 23 cases of diffuse gliomas, which included fibrillary astrocytomas (DAs, n=14), oligodendroglial tumors (n=7), and angiocentric gliomas (AGs, n=2). The study utilized SNP arrays and FISH to detect MYB rearrangements, and quantitative RT-PCR and immunohistochemistry (IMHC) to analyze MYB expression levels. Results revealed increased MYB expression in both AGs, with one AG showing a focal deletion in the 3' terminal region of MYB. Overall, increased MYB expression by RT-PCR was seen in 8 LGGs, including 5 DAs, 2 AGs, and 1 oligodendroglioma, and all three cases with MYB copy number aberrations. IMHC revealed an increase in MYB expression at the protein level in 60% of LGGs) including 41% of PAs, and 19% of HGGs. Notably, genomic abnormalities were exclusively observed in diffuse gliomas.The findings suggest that MYB dysregulation may contribute to pediatric gliomas through various mechanisms beyond amplification and deletion.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4900" ], "proposition": "#/proposition/civic.proposition:DSNTyeD_TBtfk0_UyNXeQGGTwDWyrFAk", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:11776": { "id": "civic.eid:11776", "type": "Statement", "description": "Histological, molecular, and clinical analysis of 26 histologically prototypical isomorphic diffuse gliomas with a specific DNA methylation profile distinct from other glial/glio-neuronal brain tumors and normal hemispheric tissue were found to be most closely related to pediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. IDH1/2-wildtype status was verified by Sanger sequencing of 24 cases with sufficient DNA. Integrating copy number and RNA sequencing data demonstrated MYBL1 (n=14) or MYB (n=6) alterations in 77% (20/26) of these tumors. Three tumors had MYB fusions with the gene partners, including HMG20A (n=1) and PCDHGA1 (n=2). These gene fusions resulted in a deletion of the C-terminal negative regulatory C-myb domain and/or a loss of the negative regulatory 3' miRNA-binding sites with an associated increase in MYB expression. Copy number analysis revealed gain or loss involving MYB in 3 tumors, including one tumor with gains involving both MYB and HMG20A resulting in two different MYB::HMG20A fusions and two tumors without MYB fusions detected. Increased MYB expression was observed in four (4/6) tumors", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4905" ], "proposition": "#/proposition/civic.proposition:bzVkCcvJ3-0AKArEemQYhXFgI0kLeGIr", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:11777": { "id": "civic.eid:11777", "type": "Statement", "description": "Comprehensive molecular studies (through whole genome, whole exome, transcriptome sequencing, genome-wide copy number analysis, clustering analysis by DNA methylation profiling, mutation hotspot analysis by Sanger sequencing, and FISH) were performed in a cohort of 91 low-grade neuroepithelial tumors (LGNTs), including diffuse astrocytomas, angiocentric gliomas, gangliogliomas, dysembryoplastic neuroepithelial tumors, oligodendrogliomas, and oligoastrocytomas. Molecular alterations were detected in 31/32 (97%) of LGNTs with an astrocytic morphology, including 17 diffuse astrocytomas and 15 angiocentric gliomas, and no IDH mutations were detected in these tumors. MYB (n=5) or MYBL1 (n=2) rearrangement fusions were detected in 41% (7/17) of diffuse astrocytomas, while the remaining tumors had alternations involving BRAF (n = 4), FGFR1/3 (n = 4), and others (n = 2). The gene partners involving MYB fusions in diffuse astrocytomas included PCDHGA1, LOC154902, and MMP16 and the gene parterners involivng MYBL included MMP16. In contrast, a MYB fusion (most frequently MYB::QKI) characterized almost all angiocentric gliomas (14\u201315). Only one other tumor across the series (an oligodendroglioma) had a MYB fusion (MYB::MAML2). MYB/MYBL-altered LGNTs clustered together with methylation profiling. The findings in LGNT with a predominantly astrocytic phenotype associating with MYB/MYBL alterations suggest a role of MYB/MYBL in these tumor categories with distinct characteristics.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4901" ], "proposition": "#/proposition/civic.proposition:sjZpnHJxwaTvHNsF-zn59QXFSF5NX2kx", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11778": { "id": "civic.eid:11778", "type": "Statement", "description": "The study compiled the clinicopathologic and molecular features of 46 gliomas with a MYB or MYBL1 alteration diagnosed at a single center. The tumors showed low-grade histopathologic features and were broadly classified as diffuse astrocytoma (n = 11) or angiocentric glioma (n=35). Molecular alterations interrogated by immunohistochemistry (n=46), RNA sequencing (n=29), FISH (n=24), or PCR-based sequencing (n=11) revealed MYB (n=44) or MYBL1 (n=2) alterations in all tumors. None had alterations in IDH1, IDH2, TP53, ATRX, or histone H3 genes. Regardless of histopathologic diagnosis or anatomic location, DNA methylome profiling on 35 MYB/MYBL1-altered gliomas formed a single cluster, supporting that MYB/MYBL1-altered gliomas represent a single disease entity with a range of clinical and pathologic characteristics. Of the 11 diffuse astrocytomas with MYB (n=9) and MYBL1 (n=2) rearrangements, 9 had identified gene partners, including PCDHGA1 (n=5), LOC154902 (n=1), MMP16 (n=1), and MAML2 (n=1) with MYB and MMP16 (n=1) with MYBL1.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4906" ], "proposition": "#/proposition/civic.proposition:sjZpnHJxwaTvHNsF-zn59QXFSF5NX2kx", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11779": { "id": "civic.eid:11779", "type": "Statement", "description": "Comprehensive molecular studies (through whole genome, whole exome, transcriptome sequencing, genome-wide copy number analysis, clustering analysis by DNA methylation profiling, mutation hotspot analysis by Sanger sequencing, and FISH) were performed in a cohort of 91 low-grade neuroepithelial tumors (LGNTs), including diffuse astrocytomas, angiocentric gliomas, gangliogliomas, dysembryoplastic neuroepithelial tumors, oligodendrogliomas, and oligoastrocytomas. Molecular alterations were detected in 31/32 (97%) of LGNTs with an astrocytic morphology, including 17 diffuse astrocytomas and 15 angiocentric gliomas, and no IDH mutations were detected in these tumors. MYB (n=5) or MYBL1 (n=2) rearrangements were detected in 41% (7/17) of diffuse astrocytomas, while the remaining tumors had alternations involving BRAF (n = 4), FGFR1/3 (n = 4), and others (n = 2). The gene partners involving MYB fusions in diffuse astrocytomas included PCDHGA1, LOC154902, and MMP16, and the gene partners involving MYBL1 included MMP16. In contrast, a MYB fusion (most frequently MYB::QKI) characterized almost all angiocentric gliomas (14 of 15). Only one other tumor across the series (an oligodendroglioma) had a MYB fusion (MYB::MAML2). MYB/MYBL-altered LGNTs clustered together with methylation profiling. The findings in LGNT with a predominantly astrocytic phenotype associating with MYB/MYBL alterations suggest a role of MYB/MYBL in these tumor categories with distinct characteristics.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4901" ], "proposition": "#/proposition/civic.proposition:qQwTdJwlCKQOuCUC3khR99DG4Z2ON8mh", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:11780": { "id": "civic.eid:11780", "type": "Statement", "description": "Histological, molecular, and clinical analysis of 26 histologically prototypical isomorphic diffuse gliomas with a specific DNA methylation profile distinct from other glial/glio-neuronal brain tumors and normal hemispheric tissue were found to be most closely related to pediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. IDH1/2-wildtype status was verified by Sanger sequencing of 24 cases with sufficient DNA. Integrating copy number and RNA sequencing demonstrated MYBL1 (n=14) or MYB (n=6) alterations in 77% (20/26) of these tumors. Nine tumors had MYBL1 rearrangements (including one involving 5\u2019 of MYBL1) with various gene partners, including MMP16 (n=3), RAD51B (n=1), MAML2 (n=1), ZFHX4 (n=1), TOX (n=1), RP11-586K2.1 (intergenic region) (n=1), and RP11492M23.2 (intergenic region) (n=1). These fusions resulted in a deletion of the C-terminal negative regulatory C-myb domain of MYBL1. Copy number analysis revealed gain or loss involving MYBL1 in 10 tumors, including six with MYBL1 fusion and four without MYBL1 fusions detected. Increased MYBL1 expression was observed in 71% (10/14) of the tumors with MYBL1 alterations.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4905" ], "proposition": "#/proposition/civic.proposition:Q4ijzkLI2a1n83-YnpnkMelcEPZXoMuc", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11781": { "id": "civic.eid:11781", "type": "Statement", "description": "Copy-number analysis was performed on 44 diffuse pediatric low-grade gliomas (PLGGs) to identify recurrent alterations. The most significant event, focal 8q13.1 gain, was observed in 28% (5/18) of diffuse astrocytoma grade IIs (DA2). All five DA2 samples with 8q focal gains exhibited a common centromeric breakpoint within MYBL1 after exon 9, resulting in partial duplication of MYBL1 with truncation of its C-terminal negative-regulatory domain. Whole-genome sequencing of a MYBL1-rearranged DA2 demonstrated MYBL1 tandem duplication with the telomeric sequence located in MMP16. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional DA2s with MYBL1 partial duplication. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas (AGs) in the related gene MYB on 6q23.3. The results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4907" ], "proposition": "#/proposition/civic.proposition:qQwTdJwlCKQOuCUC3khR99DG4Z2ON8mh", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11786": { "id": "civic.eid:11786", "type": "Statement", "description": "The study evaluated FOS and FOSB immunohistochemistry (IHC) in osteoid osteoma (n=23), osteoblastoma (n=22), and other bone tumor types to gauge the specificity of FOS/FOSB IHC for diagnosing these tumor types. Control groups included reactive bone lesions, proliferative bone lesions, giant cell tumor of bone, aneurysmal bone cyst, chondromyxoid fibroma, osteosarcoma, chondroblastoma, and clear cell chondrosarcoma. Strong nuclear expression of FOS was observed in all osteoid osteomas (22 of 22) and 57% of osteoblastomas (12 of 21), but was rare in the control cases (3/197). FOS rearrangements were present in 94% of osteoid osteomas and osteoblastomas, with an 86% concordance between FISH and IHC. Two osteoblastomas (5%) were positive for FOSB, but FISH did not reveal any FOSB rearrangements in these cases. The study concluded that FOS IHC can be used to diagnose osteoid osteoma and osteoblastoma. FISH could be employed in cases where low-level or focal FOS expression causes diagnostic challenges.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4912" ], "proposition": "#/proposition/civic.proposition:8kGQl9iw9mTX8LlhTspQFMjsTHsCWXMX", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:11787": { "id": "civic.eid:11787", "type": "Statement", "description": "This study investigated two cases of osteoblastoma to identify genetic aberrations using cytogenetic analysis, RNA sequencing, and molecular analyses. In the first case, a FOS::ANKH fusion transcript was identified, where exon 4 of the FOS gene was fused with sequences from intron 1 of the ANKH gene. In the second case, a FOS::RUNX2 fusion transcript was detected, involving the fusion of exon 4 of FOS with sequences from intron 5 of the RUNX2 gene. In both fusion events, the fusion introduced a stop codon and removed sequences involved in the regulation of FOS expression.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4913" ], "proposition": "#/proposition/civic.proposition:KmwnThm7PwV-1lWkLRj5FJ53tUunXd_P", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:11790": { "id": "civic.eid:11790", "type": "Statement", "description": "A research study performed in 2010 involved 57 pediatric low-grade gliomas (LGGs) and a comparison group of 59 pediatric high-grade gliomas (HGGs). Among the LGG group, there were 34 cases of pilocytic astrocytomas (PAs) and 23 cases of diffuse gliomas, which included fibrillary astrocytomas (DA, n=14), oligodendroglial tumors (n=7), and angiocentric gliomas (AG, n=2). The study utilized SNP arrays and FISH to detect MYB rearrangements and quantitative RT-PCR and immunohistochemistry (IMHC) to analyze MYB expression levels. Gains involving MYB and MYB amplifications that upregulate MYB RNA and protein expression were demonstrated in 2/14 diffuse astrocytomas (DAs). No MYB fusions were detected in the two DAs, but the sequence from one DA was found to terminate within MYB exon 9. In addition, the study revealed increased MYB expression in both AGs, with one AG showing a focal deletion in the 3' terminal region of MYB. Overall, increased MYB expression by RT-PCR was seen in 8 LGGs, including 5 DAs, 2 AGs, and 1 oligodendroglioma, and in all three cases with MYB copy number aberrations. IMHC revealed an increase in MYB expression at the protein level in 60% of LGGs including 41% of PAs, and 19% of HGGs. Notably, genomic abnormalities were exclusively observed in diffuse gliomas. The findings suggest that MYB dysregulation may contribute to pediatric gliomas, particularly in diffuse gliomas, through various mechanisms beyond amplification and deletion.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4900" ], "proposition": "#/proposition/civic.proposition:sjZpnHJxwaTvHNsF-zn59QXFSF5NX2kx", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:11867": { "id": "civic.eid:11867", "type": "Statement", "description": "Ba/F3 transformed cells harboring RET D898_E901del, T930K, T930P, or M918T mutations were shown to be sensitive to the highly selective RET inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) in a 2-day proliferation assay. Selpercatinib/pralsetinib IC50s were 12.9/11.4 nM for RET D898_E901del, 1.7/2.2 nM for T930K, 9.1/10.7 nM T930P, and 11.4/12.2 for M918T. These RET inhibitors also reduced the ERK phosphorylation induced by RET D898_E901del or RET M918T when expressed in NIH 3T3 cells.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4870" ], "proposition": "#/proposition/civic.proposition:i3ElVAJJTevoZVBJR09PVcDMgtyYKvFV", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:11876": { "id": "civic.eid:11876", "type": "Statement", "description": "Preclinical data demonstrated Ba/F3 cells transformed with RET p.M918T were sensitive to selpercatinib with an IC50 of 5nM. M918T was included as a positive control for other variants that were being tested for sensitivity to selpercatinib.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4954" ], "proposition": "#/proposition/civic.proposition:G30hHzfJzFCMLUvFhQgIzzwJ9Woe4ACX", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:12077": { "id": "civic.eid:12077", "type": "Statement", "description": "The authors reviewed histologically diagnosed astroblastomas at the National Institute of Mental Health and Neurosciences (Bangalore, India) between 2011 and 2018. Eight cases were identified and were tested with an MN1 break-apart FISH assay. Five of the eight cases demonstrated evidence of a 'break-apart' pattern, from which an MN1 alteration was inferred. Two of the five cases with MN1 alteration by FISH exhibited low-grade histology. The remaining three cases showed features of high-grade histological features, of which two recurred.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5055" ], "proposition": "#/proposition/civic.proposition:YSZO7df1PvVnoDkxBQy3FQXmDVRnVdB3", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12078": { "id": "civic.eid:12078", "type": "Statement", "description": "10 of 27 cases of histologically defined astroblastomas studied demonstrated an inferred MN1 rearrangement by break-apart FISH testing. Of these, all eight cases with material available for methylation profiling were classified as 'high-grade neuroepithelial tumor with MN1 alteration' (HGNET-MN1). Chromosome copy number profiles were analyzed using the methylation array data and notable losses included chromosomes 22q (in 1 of 8 cases), 14 (in 3 of 8 cases), and broad regions of X (in 2 of 8 cases). All cases harbored an unmethylated MGMT promoter region. A mixture of low- and high-grade histology was observed, with characteristic histological features including increased vascular and general hyalinization/sclerosis, with an absence of eosinophilic granular bodies. OLIG2 immunostaining was positive in a majority of cases (8 of 10), with a striking female preponderance (9 of 10) noted.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3560" ], "proposition": "#/proposition/civic.proposition:HoPmN0GuQOF_sGHExod4BPFTGjHG5ijD", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12079": { "id": "civic.eid:12079", "type": "Statement", "description": "In an analysis of 27 histologically defined astroblastomas, 10 had MN1 rearrangements, 7 had BRAF p.V600E mutations, 2 had RELA rearrangements, and 8 had none of these drivers identified. Astroblastoma, MN1-altered showed significantly increased overall survival compared to those histologically defined astroblastomas with BRAF p.V600E mutations (p=0.013). When compared to histologically defined astroblastomas without driver mutations, overall survival in astroblastoma, MN1-altered was increased but did not reach statistical significance due to the low number of patients. The mean overall survival of astroblastoma MN1-altered was 138\u2009months (68 to 221\u2009months, n=7) compared to 2 to 141 months (mean, 61 months; n = 7) for patients with BRAF V600E. Given the favorable prognosis, the authors suggest a more conservative approach in this tumor type.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3560" ], "proposition": "#/proposition/civic.proposition:RNYwWypHFDo_mjKbbSk40lffYjXgKU_N", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12157": { "id": "civic.eid:12157", "type": "Statement", "description": "In this phase III trial, 291 patients (12 years or older) with medullary thyroid cancer harbouring RET mutations were enrolled. Patients were randomized in a 2:1 ratio to receive selpercatinib (n=193) or cabozantinib/vandetanib (control group, n=98). \n\nProgression-free survival in the selpercatinib group was 86.8% (95% CI, 79.8-91.6) and 65.7% (95% CI, 51.9-76.4) in the control group at 12 months. Additionally, median treatment failure-free survival was not reached in the selpercatinib group and was 13.9 months in the control group (HR 0.25, 95% CI, 0.15-0.42, p <0.001), as assessed by blinded independent central review. Treatment failure-free survival at 12 months was 86.2% (95% CI 79.1-91.0) in the treatment group, and 62.1% (95% CI, 48.9-72.8) in the control group. Finally, the ORR in the treatment and control group was 69.4% (95% CI, 62.4-75.8) and 38.8% (95% CI, 29.1-49.2) respectively. \n\nOverall, treatment with selpercatinib resulted in significantly better PFS compared to cabozantinib/vandetanib treatment in patients with advanced RET-mutant medullary thyroid cancer.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5115" ], "proposition": "#/proposition/civic.proposition:qiRbY-a1f6LSXgz9HHDBH0cyhGl5-ATm", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:12173": { "id": "civic.eid:12173", "type": "Statement", "description": "In this 2022 study, the authors highlighted the diagnostic significance of different types of CEBPA mutations in 4,708 adult AML patients, recruited into the Study Alliance Leukemia trials and spanning a broad age range from under 30 to over 70 years. The study differentiated patients with CEBPA mutant AML based on mutation type: among 240 CEBPA mutant AML cases (5.1% of all cases), 60 had a single mutation in the N-terminal transactivation domains (CEBPAsmTAD), 49 had a single mutation in the C-terminal DNA-binding basic leucine zipper region (CEBPAsmbZIP), and 131 had both N-terminal TAD and C-terminal bZIP mutations (biallelic CEBPA, or CEBPA bi). Patients with CEBPAbi or CEBPAsmbZIP mutations showed distinct clinical characteristics compared to CEBPAsmTAD and CEBPA wild-type cases, including younger age and higher white blood cell counts at diagnosis. The study underscores the value of detailed CEBPA mutation analysis in AML diagnosis, by showing that CEBPAsmbZIP and CEBPA-bi define molecular subtype of disease with unique biologic and clinical characteristics, while CEBPAsmTAD represent non-specific changes.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5127" ], "proposition": "#/proposition/civic.proposition:15Cxz4mMhMKTXfd-Peee_0CL7-tWHWvz", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12174": { "id": "civic.eid:12174", "type": "Statement", "description": "In this 2022 study, the authors investigated the diagnostic significance of CEBPA mutations in AML, focusing on data from a large cohort of 1,028 patients aged 70 years or younger from the Japanese Multi-center Collaborative Sequencing Program. The study underscores that the location of CEBPA mutations is crucial in identifying specific AML subtypes. Among the 1,028 patients, 59 had a CEBPA single mutation (CEBPAsm) and 103 had a CEBPA double mutation (CEBPAdm). Of the CEBPAdm cases, 91.3% (94 of 103) had one mutation in the basic leucine zipper (bZIP) domain, while 32.2% (19 of 59) of the CEBPAsm cases had a bZIP mutation.\n\nThe study reinforces the role of CEBPA mutational analysis as an essential diagnostic tool in AML, particularly in differentiating between single and double mutations and their locations within the gene. The presence of bZIP mutations, whether single or double, provides unique diagnostic markers and refines risk stratification, aiding in developing more personalized treatment strategies for AML patients based on their specific CEBPA mutation profile.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5128" ], "proposition": "#/proposition/civic.proposition:AP5HckHCsHLi3uZdlVOuxa_Uoq4q4noO", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12200": { "id": "civic.eid:12200", "type": "Statement", "description": "In this 2019 study, the authors investigated the diagnostic significance of CEBPA mutations in AML by analyzing how the order of these mutations influences disease development in a mouse model that replicates human AML transcriptionally and morphologically. The study reveals that when CEBPA mutations occur before CSF3R mutations, they drive leukemogenesis by blocking myeloid differentiation, resulting in AML. Enhancer and transcription factor motif analysis demonstrated that wild-type CEBPA activates differentiation-related enhancers, while mutant CEBPA disrupts this pathway. Additionally, RNA-seq data show that CSF3R mutations alone promote differentiation, whereas early CEBPA mutations lead to a stem/progenitor-like phenotype with heightened cell cycle activity. In mouse models, cells with early CEBPA mutations progress to aggressive, immature leukemia, contrasting with the slower, partially differentiated progression seen with initial CSF3R mutations. These findings underscore the role of CEBPA mutations as primary oncogenic events in AML pathogenesis.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5129" ], "proposition": "#/proposition/civic.proposition:4-awY5a6ugy2clTkse8rQUaQymf6lSSA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:12327": { "id": "civic.eid:12327", "type": "Statement", "description": "This is the first case report of cribriform neuroepithelial tumor (CRINET), a rare brain cancer identified in a 26-month-old girl and a 10-month-old boy, affecting the third and fourth ventricles. Histologically, CRINET is a non-rhabdoid neoplasm with cribriform strands and a trabecular pattern, distinct from atypical teratoid/rhabdoid tumors (AT/RT). Immunohistochemistry revealed a loss of nuclear INI1 (encoded by SMARCB1) expression in tumor cells, while surrounding vascular cells and infiltrating lymphocytes demonstrated a normal pattern of retained staining. Fluorescence in situ hybridization (FISH) detected no structural alterations at the SMARCB1 locus in 22q11.2. However, sequencing of SMARCB1 identified a homozygous 4-bp duplication within exon 4 (492dupCCTT), causing a premature stop codon in one case, with no mutations found in the other. In conclusion, CRINET is a non-rhabdoid intraventricular and periventricular intracranial tumor characterized by loss of INI1 expression.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5191" ], "proposition": "#/proposition/civic.proposition:WkZahwLfqSSrZ8FT4E7hvlCuYAn9uGtw", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:12328": { "id": "civic.eid:12328", "type": "Statement", "description": "This study explored the molecular features of cribriform neuroepithelial tumors (CRINET) using multiplex ligation-dependent probe amplification (MLPA) and molecular inversion profiling (MIP) assays alongside targeted sequencing. The analysis included 3 cases that exhibited the characteristic CRINET feature of INI1 protein loss (encoded by SMARCB1 on 22q11.2). MLPA and SMARCB1 sequencing identified an allelic loss on 22q with an exon 4 CCTT duplication (492dupCCTT) in case 1 and a p.T381R mutation in case 3. A homozygous deletion of exons 7 and 8 of SMARCB1 was found in case 2. MIP analysis revealed a stable genomic profile, with no large chromosomal changes beyond 22q loss, though copy number gains were detected in several cancer genes in individual cases. Collectively, this study confirmed previous findings that identify SMARCB1 as the key gene in CRINET pathogenesis.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5192" ], "proposition": "#/proposition/civic.proposition:bLJMTICxLInRH0TKMzg_3vKxgtvcTpu6", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:12332": { "id": "civic.eid:12332", "type": "Statement", "description": "This study compared cribriform neuroepithelial tumor (CRINET) and atypical teratoid/rhabdoid tumor (AT/RT) to determine whether CRINET is a distinct entity or a variant of AT/RT. The study contained 10 CRINET samples, including 6 previously reported cases, and 30 AT/RT samples, with 10 samples from each of the three AT/RT subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC). Molecular profiling used Infinium HumanMethylation450 arrays, SMARCB1 fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and sequencing. Additionally, the survival outcome of the CRINET cohort was compared to a larger cohort of 27 patients with ATRT-TYR. Anatomical sites of CRINETs included supratentorial, infratentorial and lateral ventricle locations. CRINET cases showed diverse SMARCB1 alterations in copy number and mutations. 9 of 10 cases of CRINET harboured large heterozygous chr22q deletions inclusive of the SMARCB1 gene, with SMARCB1 mutations in the other allele in 5 cases (2 of which were germline). Methylation profiling placed CRINET within the AT/RT-tyrosinase (TYR) subgroup. Histologically, CRINET exhibited distinct morphology from AT/RT-TYR, although all CRINET cases and 9/10 AT/RT-TYR cases showed immunohistochemical staining for tyrosinase. Clinically, CRINET patients (n=10) showed better survival than ATRT-TYR patients (n=27). Mean overall survival was 125 months (95% CI: 100\u2013151) for CRINET and 53 months (95% CI: 33\u201374) for ATRT-TYR. This study highlights key histopathologic and prognostic differences between CRINET and AT/RT-TYR. The results show that CRINET should be considered a separate entity although SMARCB1 abnormalities play the key role in pathogenesis of both AT/RT and CRINET.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5193" ], "proposition": "#/proposition/civic.proposition:BZt6reu-yHtUfMIjSkbU8n9Gw-OvbksO", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Case study", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "C" }, "mappings": [ { "coding": { "name": "clinical case study evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000008" }, "relation": "exactMatch" } ] } }, "civic.eid:12397": { "id": "civic.eid:12397", "type": "Statement", "description": "This 2017 study is result of collaboration of multiple institutions and was led by St. Jude Children's Research Hospital team. The total cohort of 3115 B-ALL patients (all ages) was studied, with 212 with expression profile of BCR::ABL1-like B-ALL (based on gemone and/or transcriptome sequencing). 19 out of 212 cases (8.9%) revealed 4 types of EPOR rearrangements: insertion of EPOR distal to the IGH enhancer (73.7%), insertion of EPOR into IGK at 2p11.2 (10.5%), cytogenetically visible t(14;19)(q32;p13) (10.5%), and insertion of EPOR upstream of LAIR1 (leukocyte-associated immunoglobulin-like receptor 1) at 19q13 (5.3%). The authors demonstrated that all these EPOR rearrangements resulted in truncation of the cytoplasmic tail of EPOR with preservation of Y368 tyrosine residue essential for receptor activation and loss of distal regulatory tyrosine residues (Y426, Y454, Y456, Y504) and resulted in JAK/STAT signaling activation (potential for treatment). All EPORr cases showed no expression distal to the rearrangement by ex8 specific assay (potential for screening). Interestingly, the authors used 3 EPORr cases to isolate leukemic, stem cell, progenitor, mature cell populations to test for EPORr, which was identified not only in blasts, but also in CD33+ myeloid cells (all 3 cases), myeloid progenitors (1 case), and even in normal B-cell obtained at the time of remission in 1 case. The study described genomic structure of EPOR rearrangements in B-ALL and confirmed their association with B-ALL with BCR::ABL1-like features.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2824" ], "proposition": "#/proposition/civic.proposition:xEvTVG7xFEQOzWOPViDUY157i4enMLkY", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12399": { "id": "civic.eid:12399", "type": "Statement", "description": "In this study, 17 patients with a variant pericentric inv(3) were identified from an institutional cytogenetics database, out of283 myeloid neoplasms with a MECOM rearrangement (MECOM-R) confirmed by FISH,. Patients are 13 males and 4 females, with an age range 42-85 yrs, median age 67 yrs, and diagnosed with AML (n=15), MDS (n=1) and CMML (n=1). Using metaphase FISH with commercially available MECOM dual color breakapart DNA probes, chromosomal breakpoints were identified at 3p23 (n=11), 3p25 (n=3), 3p21 (n=2) and 3p13 (n=1), in addition to the 3q26.2 breakpoint leading to MECOM-R. These pericentric inversions (inv(3)) detected by metaphase FISH were missed by initial karyotyping in 16 of the 17 cases. Somatic mutations were detected with NGS-based analysis on an 81-gene panel. Similar to classic/ paracentric inv(3)/GATA2::MECOM-R, pericentric inv(3) patients in this showed cytopenia, morphological dysplasia of megakaryocytes, -7/del(7q) and dismal outcomes (mean OS of 14 months). Unique features such as thrombocytopenia (15/17; 88%), increased monocytes in peripheral blood (15/17; 88%), and decreased megakaryocytes (11/17; 65%) were also observed. An average of 3 mutation events per case were identified in the study cohort which is higher than the average of 2 mutation events per case in classic inv(3)/t(3;3). The highest frequency of mutations was detected in gene NRAS (35%), followed by RUNX1, FLT3, ASXL1, PTPN11, SF3B1 and TP53. These 7 genes accounted for 53% of the mutation events. Mutations in SF3B1 are reported more commonly in the classic inv(3)/t(3;3) cases and were found in only 3 cases of pericentric inv(3)/MECOM-R cohort. As pericentric inv(3)s are subtle/ cryptic, reflex MECOM-R BAP FISH is recommended in myeloid neoplasms showing -7/del(7q), an aberration found at a high frequency of 75% in this study. Detection of pericentric inv(3) with MECOM-R may change the classification of the neoplasm from intermediate-risk to high-risk and the diagnosis from MDS to AML in some cases. In summary, the study shows that atypical 3q26/MECOM\u2013R with loci in the p arm of chromosome 3 result in leukemia with the same clinical and pathology characteristics as the classical inv(3)/t(3;3)(q21q26), and may be classified together as a single entity of MECOM-rearranged AML.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5237" ], "proposition": "#/proposition/civic.proposition:t4EpzOy7YxAlgVuOAluIfn8eDD5TlIQk", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12400": { "id": "civic.eid:12400", "type": "Statement", "description": "This study evaluates the frequency of MECOM rearrangements by fluorescence in situ hybridization (FISH) in 76 AML and 21 MDS patients with various 3q chromosomal aberrations. Patients were referred to four institutions in Italy (in Bologna, Ferrara, Padova, Rovigo) between 1995-2014. MECOM rearrangements were found in 51 of the 97 patients (54.8%) most of which showed 3q26 involvement by chromosome banding analysis (CBA). Of the 51 patients: 26 patients showed inv(3)/t(3;3) and 15 patients showed other balanced 3q26 translocations (t(3q26)). Of the remaining 10 patients with various 3q abnormalities (10.3%), 5 showed balanced translocations involving 3q21 or 3q25 and leading to RPN1/MECOM rearrangement, 2 showed intrachromosomal gene amplification leading to MECOM overexpression, and 3 patients were missed for 3q26 involvement by CBA due to suboptimal quality of chromosome morphology during sample preparation. All cases showed MECOM overexpression by real-time quantitative PCR. Detection of such cryptic MECOM rearrangements by FISH in this study suggests that the frequency of MECOM involvement in myeloid malignancies is underestimated. The study showed that AML with variant MECOM rearrangements has same characteristics as AML with classic inv(3)(q21q26). As MECOM rearrangements are associated with very short overall survival (OS) and poor prognosis, patients with any 3q abnormalities should be screened for MECOM rearrangement.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5238" ], "proposition": "#/proposition/civic.proposition:t4EpzOy7YxAlgVuOAluIfn8eDD5TlIQk", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12401": { "id": "civic.eid:12401", "type": "Statement", "description": "In this study, samples from 33 patients presenting with AML or MDS were collected from either the Erasmus Hematology Department biobank (The Netherlands) or from the Munich Leukemia Laboratory (Germany). Multiple assays were used for sample characterization including metaphase karyotyping, MECOM interphase FISH,quantitative real-time PCR on mRNA, SNP array analysis, sequencing of the targeted chromosomal region 3q21.1-3q26.2 (3q-capture), RNA sequencing (RNA-seq), exome sequencing and whole genome sequencing.. 33 patients with atypical 3q26 rearrangements were identified and 25 of those showed MECOM involvement. Among these 25, losses or gains on 3q26 or on partner loci were seen in 7 cases, and no copy number losses or gains were seen in 12, indicative of balanced translocations. 4 of the 33 cases showed amplification of 3q26/MECOM by both FISH and SNP array. Overexpression of EVI1 in 30 of the 33 atypical 3q26 cases was seen, while in 29 cases MDS-EVI1 expression level was either absent or very low. The breakpoint region in 23 of the 33 cases was identified to occur either upstream (74%) or downstream (26%) of the EVI1 gene. The translocated gene partner of MECOM/3q26 was identified in 20 of the 33 cases and involved previously reported genes (THADA, CDK6, MYC and ARID1B) as well as novel and unique partner loci such as TGFBR2, HSPA8, TCF4 among others. These genes are known to be active in myeloid cells and are involved in superenhancer hijacking by the MECOM locus. These translocated enhancers contact and coactivate the promoter of EVI1 but not the promoter of MDS-EVI1. In more than 50% of the 33 cases, GATA2 expression was found to be monoallelic or skewed due to cryptic GATA2/MECOM translocation. The study concludes that both atypical 3q26/MECOM and the classical inv(3)/t(3;3)(q21q26) may be classified together as a single entity of 3q26-rearranged AMLs.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5239" ], "proposition": "#/proposition/civic.proposition:63CIgLeo0rUrUUubY_wEvZ67coxUJLki", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12463": { "id": "civic.eid:12463", "type": "Statement", "description": "A cross-sectional cohort study was performed in 161 men with metastatic prostate cancer undergoing a change in treatment to determine if pre-therapy AR-V7 nuclear protein expression in circulating tumor cells (CTCs) is a treatment-specific marker for outcomes between androgen receptor signaling (ARS) inhibitors and taxanes. A multivariable model adjusting for baseline factor associated with survival showed superior overall survival with taxanes relative to ARS inhibitors when AR-V7-positive CTCs were detected pre-therapy (hazard ratio , 0.24; 95% CI 0.10-0.57; P=0.035).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5294" ], "proposition": "#/proposition/civic.proposition:1BDhq1S3vZeLI6hJCpBdkuYa1wW46dpq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12464": { "id": "civic.eid:12464", "type": "Statement", "description": "A blinded, multi-institutional cohort study was performed in 142 men with metastatic, castration-resistant prostate cancer to determine if pre-therapy nuclear-localized expression of AR-V7 protein in circulating tumor cells (CTCs) is a treatment-selective marker for outcome following treatment with either androgen receptor signaling (ARS) inhibitors or taxanes. Patients with AR-V7-positive CTCs had superior overall survival with taxanes vs ARS inhibitors (hazard ratio 0.62; 95% CI 0.28-1.39; P=.25). Patients with AR-V7-negative CTCs had superior overall survival with ARS inhibitors vs taxanes (hazard ratio 1.67; 95 CI 1.00-2.81); P=.05).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5295" ], "proposition": "#/proposition/civic.proposition:1BDhq1S3vZeLI6hJCpBdkuYa1wW46dpq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12486": { "id": "civic.eid:12486", "type": "Statement", "description": "PALOMA-3, a phase III, multicenter, double-blind randomized controlled trial enrolled patients with advanced estrogen receptor-positive breast cancer receiving fulvestrant (estrogen receptor antagonist) therapy with either palbociclib (a CDK4/6 inhibitor) (N = 347) or placebo (N = 174). Of the total number of 459 patients, 401 patients had enough DNA in pretreatment plasma samples for a custom targeted sequencing panel to assess for mutations (17 genes), copy number alterations (14 genes), and circulating tumor fraction. The prevalence of copy number alterations was assessed only in samples with more than 10% circulating tumor fraction (N=156). Gain of copy number of FGFR1 was observed in 10% (15/156) as one of the most frequent finding, together with gains of MCL1, CCND1, and MYC. In univariable analysis gains in FGFR1 were associated with poorer progression-free survival (PFS) in both treatment groups [HR=3.40, 95% CI 1.91. to 6.04, log-rank Q<0.001 for the group treated with palbociclib plus fulvestrant, and HR = 3.61, 95% CI = 1.31 to 9.97; log-rank Q=0.047 for the group treated with fulvestrant with placebo]. Since an increased circulating tumor fraction was required to detect copy number changes in plasma and higher circulating tumor fraction was also associated with worse PFS, a multivariable analysis was performed. FGFR1 gain remained statistically significant in the model [HR=2.91, 95% CI 1.61 to 5.25, p<0.001]. The median PFS of patients on palbociclib and fulvestrant with detected FGFR1 gain was 3.9 months vs 12.0 months for those without it. In addition, PFS of patients with FGFR1 gain together with TP53 mutations was at 3.7 months. There was no statistically significant interaction for FGFR1 gain with treatment randomization.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5323" ], "proposition": "#/proposition/civic.proposition:jnJVZ7hQOw374mvXkrRm0tawWjM7BCP_", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12487": { "id": "civic.eid:12487", "type": "Statement", "description": "This study aimed to determine the amplification rates of FGFR1, FGFR2, and FGFR3 in breast cancer and evaluate their impact on prognosis. In a cohort of 894 breast cancer patients, FGFR1 amplification was present in 6.6% (33/503) of assessable tumors and was enriched in the luminal B-like subtype (69.7% of FGFR1-amplified tumors vs. 32.6% of non-amplified tumors). Due to the very low frequency of FGFR2 (<1%) and FGFR3 (<1%) amplifications, outcome analyses focused only on FGFR1 amplification.\nThe results showed that FGFR1 amplification was associated with a trend toward poorer outcomes, particularly shorter distant metastasis\u2013free survival (DMFS; p=0.04, unadjusted analysis); however, this difference did not reach statistical significance in analysis adjusted for other well-known prognostic factors (P=0.05). No significant effect of FGFR1 amplification was observed on other secondary outcomes, including overall survival (OS) and local recurrence\u2013free survival (LRFS).\nThese findings indicate that FGFR1 amplification is disproportionately associated with luminal B-like breast cancers (luminal B-like enriched), which are typically more aggressive and have higher proliferation rates. The absence of a statistically significant prognostic association in this study is likely due to the small number of FGFR1-amplified cases (n = 33), limiting statistical power.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5325" ], "proposition": "#/proposition/civic.proposition:jnJVZ7hQOw374mvXkrRm0tawWjM7BCP_", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12494": { "id": "civic.eid:12494", "type": "Statement", "description": "In this 2005 study, immunohistochemical staining was used to assess the subcellular localization of NPM in 1,835 paraffin-embedded tumor specimens, including 591 from primary AML patients (ages 15\u201360), 135 from secondary AML patients, and 980 from hematopoietic and non-hematopoietic neoplasms other than AML. Of the 591 specimens tested, 208 (35.2%) were found to have aberrant cytoplasmic NPM localization (NPMc+), while the remainder displayed normal nuclear localization (NPMc\u2013). Subsequent RT-PCR and Sanger sequencing found 51/52 NPMc+ specimens harbored a NPM1 exon 11 (NM_002520) mutation that results in a distinct C-terminal sequence and is predicted to alter the NPM protein at its C-terminus (referred to in this study as NPM exon 12 mutations). Transfection of NIH-3T3 cells with the NPM1 mutant alleles showed aberrant cytoplasmic localization compared to wild type, demonstrating a causal relationship between NPM1 mutation status and aberrant subcellular localization. NPMc+ was found to be associated with a normal karyotype in approximately 60% of AML patients (142/230, 61.7%). FLT3 internal tandem duplications were found to be twice as frequent in NPMc+ vs. NPMc- specimens, suggesting these mutations may be mechanistically linked. The majority of NPMc+ AML specimens were CD34- (49/52) and had a wide morphologic spectrum, demonstrating multilineage involvement. Finally, the authors investigated the response to induction therapy in 126 patients with AML and a normal karyotype (79 NPMc+, 47 NPMc-) treated according to the GIMEMA LAM99P protocol. AML patients with a normal karyotype and NPMc+ were found to have a relatively good response to induction chemotherapy. The study illustrates that AML cases characterized by NPM1 mutations represent a unique disease subtype with shared morphologic features, immunophenotype and molecular and clinical characteristics.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:130" ], "proposition": "#/proposition/civic.proposition:FieV3ZZI2vPPWcQmyJlvN8LRCQQ-4qWW", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12495": { "id": "civic.eid:12495", "type": "Statement", "description": "In this 2005 study, the authors investigated the prevalence and prognostic impact of NPM1 mutation status in 300 adult patients with AML (16-60 years of age) with normal cytogenetics. The diagnostic bone marrow or peripheral blood sample of these 300 patients were analyzed and included the following: 257 patients with de novo AML, 24 patients with t-AML/s-AML, and 19 patients with no available information. NPM1 exon 11 mutations (referred to in this study as NPM exon 12 mutations) were identified in 145/300 (48%) of the specimens tested, representing the most frequent molecular event that has been identified in AML patients with a normal karyotype to-date. The majority of identified NPM1 mutations resulted in a 4 base pair insertion. Universally all mutations resulted in protein elongation and replacement of the last 7 amino acids in NPM1. Mutation status for FLT3, CEPBA, and MLL were also assessed. FLT3 internal tandem duplications (ITDs) and tyrosine kinase domain mutations (TKDs) were more frequently identified in the NPM1-mutated group (41% and 15% respectively) compared to the NPM1 negative group (25% and 5% respectively). NPM1-mutated/FLT3 ITD-negative mutation status was significantly associated with induction success and arose as a prognostic marker for achievement of complete remission (odds ratio = 2.81, 95% CI = 1.39-5.69). In addition, NPM1-mutated/FLT3 ITD-negative patients had significantly better relapse-free survival and overall survival. In summary, NPM1 mutations were frequent in AML and were associated with specific clinical (favorable outcome) and genetic characteristics (normal cytogenetics and FLT3 mutations).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:144" ], "proposition": "#/proposition/civic.proposition:FieV3ZZI2vPPWcQmyJlvN8LRCQQ-4qWW", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12497": { "id": "civic.eid:12497", "type": "Statement", "description": "Amplification of FGFR1 is one molecular alteration associated with hormonal resistance and relapse in breast cancer. Using two different patient data cohorts (H12O - patients diagnosed at Hospital 12 de Octubre [n = 251] and METABRIC [n=98 patients]) with hormone-positive breast cancer (HRPBC), FISH studies demonstrated FGFR1 amplification in 11.8% of H12O patients. This was validated in the METABRIC cohort, where 7.6% of HRPBC demonstrated FGFR1 amplification. Furthermore, both studies found that FGFR1 amplification was more common in luminal B (16.3% H12O, 11.1% METABRIC) versus luminal A (6.6%, 5.5%) subtype. Using the H12O cohort, RNA expression analysis revealed 17% of cases had FGFR1 overexpression. Cumulatively, 24.5% of patients had altered FGFR1 expression as measured by FISH (amplification) and/or RNA expression (overexpression).\u00a0From the H12O cohort, the median relapse-free survival time for patients with FGFR1-amplification was 9.3 years, which is significantly lower than the median relapse-free survival time for patients with non-FGFR1-amplified breast cancer (11.2 years). From the METABRIC cohort, the median relapse-free survival for patients with FGFR1-amplified breast cancer was 12.2 years, which is lower than patients without the FGFR1-amplication in which the median relapse-free survival was 21.1 years. The discrepancy between the median relapse-free survival rates between the cohorts, might be attributed to the demographic and clinical characteristics of the patients in each cohort, with the patients in the METABRIC being slightly older and having earlier stage breast cancer (T1/T2 and N0/N1 stages) than the H12O cohort. However, in both cohorts, when breast cancer was sub-classified by luminal type A or B, the difference in the relapse-free survival time between FGFR1-amplified and non-amplified was no longer significant. When median relapse-free survival included patients with FGFR1 amplification and/or FGFR1 overexpression, the average relapse free survival was 8.8 years for versus 11.2 from non-amplified/non-overexpressed. This analysis combining amplification and overexpression was not performed on the luminal subtypes. In conclusion, FGFR1 amplification is found in HRPBC, more often in the luminal B subtype, and is associated with worse prognosis in HRPBC, however the prognostic consequences of FGFR1 amplification are lost when HRPBC is classified by luminal subtypes.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5332" ], "proposition": "#/proposition/civic.proposition:jnJVZ7hQOw374mvXkrRm0tawWjM7BCP_", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12521": { "id": "civic.eid:12521", "type": "Statement", "description": "In this Swedish population-based study, the authors retrospectively re-evaluated 71 poorly differentiated supratentorial CNS tumors in children, previously diagnosed as CNS-PNETs, to assess their molecular features, including BCOR genetic alterations. The cohort included 39 males and 32 females, with a median age at diagnosis of 6.2 years. Using WHO 2021 histopathological guidelines and the Molecular Neuropathology (MNP) brain tumor classifier, 10% (n=7) of tumors were subclassified as CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2). All seven CNS NB-FOXR2 tumors showed complete concordance between histology-based diagnoses and DNA methylation-based classification, with a calibrated score (CS) \u2265 0.9.\nThe median age at diagnosis of CNS NB-FOXR2 patients was 5.3 years (range 2.5\u201315.7), with 43% males (n=3) and 57% females (n=4). Copy number analysis predicted gain of chromosome 1q in all seven tumors, and whole or partial loss of chromosome 16q in 86% (6/7) of cases. While the overall CNS-PNET cohort demonstrated poor outcomes (5-year PFS 38% \u00b111%, 5-year OS 45% \u00b112%), CNS NB-FOXR2 patients had excellent prognosis, with both 5-year PFS and OS at 100%.\nThese findings highlight that CNS NB-FOXR2 represents a rare, molecularly distinct entity within pediatric CNS-PNETs, and that DNA methylation profiling provides a reliable diagnostic tool to accurately identify this tumor type, which is associated with favorable long-term outcomes.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5347" ], "proposition": "#/proposition/civic.proposition:aW1DTrk0v0DOnN9-YfoKlGSuQu4Z3fi9", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12598": { "id": "civic.eid:12598", "type": "Statement", "description": "The Phase 3 trial for the selective and brain-penetrant RET kinase inhibitor selpercatinib in Medullary Thyroid Cancer (MTC) LIBRETTO-531 (NCT04211337) consisted of 291 total patients. \n\nThe patients had pathologically confirmed unresectable locally advanced or metastatic MTC, and had no history of treatment with kinase inhibitors. \n\nPatients had a prospectively identified pathogenic RET alteration, either somatic or germline, and 182 patients had RET M918T (~63%). \n\nFrom the patients with M918T, 121 were treated with selpercatinib, and 61 were treated with control (physician\u2019s choice of vandetanib or cabozantinib). \n\nIn the M918T subgroup analysis, control patients had median progression-free survival (PFS) of 17.5 months, while in the selpercatinib-treated patients the median PFS was not met. Hazard\u2000Ratio (95%\u2000CI) was 0.40 (0.21\u20130.77) between M918T control and selpercatinib treated patients.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5115" ], "proposition": "#/proposition/civic.proposition:5OFjQDRrBBupMmCAUFH3qIKhyjEpsB-9", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:12749": { "id": "civic.eid:12749", "type": "Statement", "description": "In this 2015 study, formalin-fixed paraffin-embedded (FFPE) tissue samples were retrieved from the diagnostic pathology archives of the Royal National Orthopaedic Hospital (RNOH) and the Basel Bone Tumour Reference Centre (BBTRC). All cases were reviewed by specialist bone tumour pathologists and classified according to World Health Organization (WHO) criteria. To investigate the oncogenic driver of Giant Cell Tumour of Bone (GCT), whole-genome sequencing was performed on five cases and whole-exome sequencing on one case. In addition, targeted hotspot sequencing using a 14-gene panel, including H3F3A and H3F3B, was conducted to assess the specificity of the p.G34W alteration. This analysis included 91 GCTs and 321 other osteoclast-rich bone lesions.\nNo driver mutations other than the H3F3A p.G34W mutation were identified in the sequenced genomes and exome. Targeted sequencing detected this mutation in 83 GCT cases, with single cases of H3F3A p.G34R and p.G34M; no mutations were found in H3F3B. Both GCTs that metastasized to the lung harbored the H3F3A p.G34W mutation. Overall, H3F3A p.G34 alterations were present in 96% (85/89) of GCTs and absent in other bone tumours in this cohort, supporting their role as highly sensitive and specific molecular markers for GCT.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5488" ], "proposition": "#/proposition/civic.proposition:w01RQBoPRIYQ1JcpgXRjgZM8BlJIn4FY", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:12750": { "id": "civic.eid:12750", "type": "Statement", "description": "In this 2015 study, formalin-fixed, paraffin-embedded (FFPE) tumor samples diagnosed between 1996 and 2014 as giant cell tumor of bone (GCTB), chondroblastoma, chondromyxoid fibroma, aneurysmal bone cyst, or telangiectatic osteosarcoma were retrieved from the Leiden University Medical Centre. A total of 75 GCTB samples were analyzed, including 15 recurrences from 12 patients. H3F3A hotspot mutations were assessed using Sanger sequencing, and immunohistochemistry for H3K36 trimethylation and ATRX expression was performed to evaluate correlation with mutation status.\nH3F3A G34W/V mutations were identified in 41 of 59 GCTBs (69%) (39 G34W, 2 G34V). Rare variants included a G34 stop codon and a TCT insertion at position 35. H3K36 trimethylation was present in 59 of 60 cases and was more frequent in mutated tumors, whereas ATRX loss showed no correlation with mutation status. Only G34W/V variants were considered mutation-positive for correlation analysis due to the uncertain significance of other variants. In conclusion, H3F3A mutation analysis (particularly G34W/V) by Sanger sequencing represents a highly specific, though less sensitive, diagnostic tool for distinguishing GCTB from other giant cell\u2013containing bone tumors.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:5489" ], "proposition": "#/proposition/civic.proposition:Yw-qND3OVkBnT7KWmdImTWa2kGdKm1TM", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:1421": { "id": "civic.eid:1421", "type": "Statement", "description": "In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 344 had V600E mutation. 174 patients were treated with vemurafenib and placebo, and 170 were treated with vemurafenib and cobimetinib and tested for progression free survival. 88 of 174 monotherapy group patients had an event with median progression free survival of 6.5 months. In the combination group 58 of 174 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.57 (0.41-0.80).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:963" ], "proposition": "#/proposition/civic.proposition:iS8NTzApX0dHrxVCjn1V2Vn_GaU6sUcB", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:1552": { "id": "civic.eid:1552", "type": "Statement", "description": "In a study of 908 patients with colorectal cancer, 45 patients had BRAF V600E mutations and 589 patients were BRAF wild type. BRAF V600E mutations were more likely to be proximal tumors (68.9%, 20.7%; p<0.0001), they were more likely to be poorly differentiated (17.7%, 1.9%; p<0.0001), they were more likely to be mucinous carcinoma type (20.0%, 4.2%; p=0.0003), they were more likely to have lymphatic invasion (77.6%, 49.9%; p=0.0003), and they had a shorter survival time (31.1 mo, 41.6 mo; p=0.001). The 3-year survival rate was significantly poorer in the V600E group when compared to the wild type group (63.8%, 87.9%; p<0.0001).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1027" ], "proposition": "#/proposition/civic.proposition:sXFJwmFRv74A8_wLpTiNttPaZo_dDR52", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:1592": { "id": "civic.eid:1592", "type": "Statement", "description": "Osimertinib has been approved for the treatment of EGFR T790M mutant NSCLC.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1053" ], "proposition": "#/proposition/civic.proposition:MzXNEXAgp9_wIjD84MT_eEV7b0n_4HG0", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:1665": { "id": "civic.eid:1665", "type": "Statement", "description": "90 NSCLC patients with stage IIIB/IV chemotherapy-resistant tumors were treated with gefitinib, and the L858R EGFR mutation was associated with longer time to treatment failure than those with wild-type EGFR (median 9.1 versus 2.1). In multivariate analysis, L858R mutations plus adenocarcinoma was a significant predictive factor for time to treatment failure (HR = 0.1030; P = .0004).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1127" ], "proposition": "#/proposition/civic.proposition:IAd8IXLDyxX3SeXoMU9ephk7bmyIgfXA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:1867": { "id": "civic.eid:1867", "type": "Statement", "description": "Randomized, international, open-label, phase 3 trial (NCT02151981) in 419 patients with T790M-positive advanced NSCLC and disease progression after first-line EGFR-TKI therapy. Patients were randomized, in a 2:1 ratio, to oral osimertinib or chemotherapy (pemetrexed plus either carboplatin or cisplatin every 3 weeks for up to six cycles, maintenance pemetrexed was allowed). Primary end point was PFS, which was significantly longer with osimertinib than with chemotherapy (10.1 months vs. 4.4 months; HR 0.30; 95% CI: 0.23 to 0.41; P<0.001). Objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with chemotherapy (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1286" ], "proposition": "#/proposition/civic.proposition:MzXNEXAgp9_wIjD84MT_eEV7b0n_4HG0", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:229": { "id": "civic.eid:229", "type": "Statement", "description": "There is no statistical difference in progression free survival between lung cancer patients treated with gefitinib or erlotinib with EGFR L858R mutations (N=72/242; univariate: P=0.283; multivariate: P=0.250) compared to patients with Exon 19 mutations (N=170).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:162" ], "proposition": "#/proposition/civic.proposition:n3Pb28gAGH-x3rHFJJ1ZaGzWeeeTK9LU", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:2451": { "id": "civic.eid:2451", "type": "Statement", "description": "In an in vitro study of imatinib sensitivity, KIT D816V was cloned into a plasmid by site-directed mutagenesis of KIT WT cDNA. Chinese hamster ovary cells were transiently transfected with the plasmid. Cells were treated with control media or media containing various concentrations of imatinib for 90 minutes. Protein lysates from the transfected cells were examined for phosphorylated tyrosine, a measure of KIT activation. Cells expressing KIT D816V were resistant to imatinib up to 10 umol/L.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:412" ], "proposition": "#/proposition/civic.proposition:IGMXe-5GMIkRAhG2J1yfSRvuSEGmXh6f", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:2621": { "id": "civic.eid:2621", "type": "Statement", "description": "In a phase 3 clinical trial of non-small cell lung cancer (NSCLC) patients, a subset of patients with EGFR mutations (n=44) treated with gefitinib were associated with improved progression free survival (HR: 0.16, 95% CI: 0.05-0.49, P=0.001), and a higher objective response rate (ORR: 42.1% vs 21.1%, p=0.04) compared to patients treated with docetaxel. Of the 44 patients, 22 had an exon 19 deletion, 16 had an L858R mutation, one patient had an exon 20 T790M mutation, two had an exon G719A mutation and four had other mutations.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1501" ], "proposition": "#/proposition/civic.proposition:IAd8IXLDyxX3SeXoMU9ephk7bmyIgfXA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:2629": { "id": "civic.eid:2629", "type": "Statement", "description": "In an in vitro study using NCI-H1666 cells (wildtype EGFR) and NCI-H3255 cells (EGFR-L858R), inhibition of cell growth was used as an assay to determine sensitivity to irreversible tyrosine kinase inhibitor (TKI) drugs. Cells with an EGFR L858R mutation demonstrated an improved response to afatinib (IC50: 0.7nM vs. 60nM) compared to wildtype EGFR cells.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1525" ], "proposition": "#/proposition/civic.proposition:3n7vu1vTbv9cSmlyrCq4fNuh_5YNzo1c", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:2634": { "id": "civic.eid:2634", "type": "Statement", "description": "In a phase 3 clinical trial of Korean, never-smoker, lung adenocarcinoma patients, a subset of patients with EGFR mutations (n=42) treated with gefitinib were associated with improved overall response rate compared to gemcitabine plus cisplatin treatment (84.6%, 22/26, vs. 37.5%, 6/16, P=0.002). By contrast, in EGFR mutation negative cases, the response rate was much lower (25.9%, 7/27). The frequency of mutation in exon 19 deletion and L858R was 64.3% (27/42) and 36.4% (16/42), respectively. Exon 19 and L858R mutations were mutually exclusive in this cohort.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1513" ], "proposition": "#/proposition/civic.proposition:PceKq2Xgfh0Yva3SbaWz18wz4HGTsA0k", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:276": { "id": "civic.eid:276", "type": "Statement", "description": "Gefinitib has been shown to be effective in treating cell lines with L858R missense mutations.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:181" ], "proposition": "#/proposition/civic.proposition:IAd8IXLDyxX3SeXoMU9ephk7bmyIgfXA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:2994": { "id": "civic.eid:2994", "type": "Statement", "description": "On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1724" ], "proposition": "#/proposition/civic.proposition:mCQYLirVeuIXrHZ2ElPCxdxLKC24cz_-", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:2997": { "id": "civic.eid:2997", "type": "Statement", "description": "Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1725" ], "proposition": "#/proposition/civic.proposition:3n7vu1vTbv9cSmlyrCq4fNuh_5YNzo1c", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:3758": { "id": "civic.eid:3758", "type": "Statement", "description": "In a clinical trial (NCT01597908) of 704 metastatic melanoma patients, patients harboring a BRAF V600E mutation and treated with vemurafenib (n=317) were associated with a 51% response rate, as compared to a 64% response rate (p<0.001) in V600E mutation positive patients treated with dabrafenib and trametinib combination therapy (n=312). Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:353" ], "proposition": "#/proposition/civic.proposition:MysT3JVamQVoYNKcWA-sHp4imvhG4azb", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:3811": { "id": "civic.eid:3811", "type": "Statement", "description": "EGFR L858R was expressed in Ba/F3 cells which do not contain endogenous EGFR, and conferred growth factor independance to the cells. Cells were plated and treated with 1st generation EGFR inhibitors Gefitinib, Erlotinib, or the the tool compound AEE788, and IC50 values were measured. L858R EGFR cells had very low IC50 nmol/L values for all three inhibitors in comparison to other constructs (Gefitinib=12, Erlotinib=6, AEE788=6), indicating sensitivity to all three constructs.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1528" ], "proposition": "#/proposition/civic.proposition:cRSqJ4wbvraPSVk1xTYvc1K54NEO3TOk", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:4181": { "id": "civic.eid:4181", "type": "Statement", "description": "In a phase 3 clinical trial (NCT01597908) involving 704 patients with metastatic melanoma harboring BRAF V600 mutations, a subgroup analysis of patients with V600K mutations showed an objective response rate of 44% in those treated with vemurafenib (n=34), compared with 65% in those treated with the combination of dabrafenib and trametinib (n=34). Across the overall study population, cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients receiving combination therapy versus 18% of those receiving vemurafenib.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:353" ], "proposition": "#/proposition/civic.proposition:hmAwYWTm5PnCptA6R0W9Nd5VnlU-M5Ik", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:4265": { "id": "civic.eid:4265", "type": "Statement", "description": "MCF-7 cells were transduced with YFP tagged EGFR with E746_A750delELREA mutation, or YFP EGFR wildtype, and stained for ectopic YFP EGFR and phospho-Akt as a readout for EGFR pathway activity. Increased p-Akt stain was seen with ectopic mutant EGFR over wildtype cells. Parallel erlotinib incubations of cells with wildtype EGFR induced recompartmentalization of ectopic EGFR protien only at high concentration (10uM). Addition of erlotinib to mutant EGFR cell incubations reduced p-Akt signal and induced recompartmentalization of ectopic EGFR protien at considerably lower concentration (100 nM) erlotinib. These results indicate the EGFR L858R variant as a growth pathway driver targetable by erlotinib.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1991" ], "proposition": "#/proposition/civic.proposition:mCQYLirVeuIXrHZ2ElPCxdxLKC24cz_-", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:4285": { "id": "civic.eid:4285", "type": "Statement", "description": "In an in vitro study, a MCF-7 cell line expressing EGFR L858R mutation demonstrated sensitivity to erlotinib or dacomitinib (PF00299804) treatment, compared to MCF-7 cells expressing EGFR wild-type. Sensitivity was determined by assessing YFP signal-EGFR relocation.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1993" ], "proposition": "#/proposition/civic.proposition:udXw1_7oBcu2fM8sH0Ce-rUpG89vMl6r", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:4290": { "id": "civic.eid:4290", "type": "Statement", "description": "In a prospective study of 46 Caucasian, advanced lung adenocarcinoma patients harboring EGFR mutations, first-line erlotinib treatment was assessed. Average PFS and OS for these 46 patients was 11 months (95% CI: 9.7-12.3 months) and 23 months (95% CI: 21.3-28.6+ months), respectively. A PFS rate of 81% at three months met the primary endpoint of presumed superiority over chemotherapy. Clinical benefit (CR+PR+SD) rate was 81%. Fifteen patients harbored EGFR L858R mutations, which was the only mutation found in exon 21. The authors note similar response profiles for exon 19 (27/46) and exon 21 mutations (15/46) to the overall population.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2067" ], "proposition": "#/proposition/civic.proposition:bnPe-psTZ15It_mcVdGqXPZ_NBKUNNp5", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:4291": { "id": "civic.eid:4291", "type": "Statement", "description": "In an in vitro study, Ba/F3 cell line expressing EGFR L858R was associated with sensitivity to erlotinib treatment (IC50 26.9 \u00b1 12.4nM). EGFR L858R was used as a positive control for comparing sensitivity to erlotinib for EGFR-RAD51 fusion. Sensitivity was determined by assessing cell viability, AKT and ERK phosphorylation, and EGFR auto-phosphorylation.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2086" ], "proposition": "#/proposition/civic.proposition:bnPe-psTZ15It_mcVdGqXPZ_NBKUNNp5", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:4846": { "id": "civic.eid:4846", "type": "Statement", "description": "Sequencing of 39 pediatric midline high-grade astrocytomas identified 5 patients with ACVR1 mutations. The authors identified an increase in endogenous phospho-SMAD1/5/8 signal in diffuse intrinsic pontine glioma (DIPG) cells harboring ACVR1 G328V, with corresponding increase in phospho-SMAD1/5/8 staining as well. By PCR, the authors show strong increase in fold change of mRNA expression in downstream proteins of the ACVR1/BMP pathway, ID, ID2, ID3 and SNAI1 in ACVR1-mutant DIPG cell line compared to glioblastoma cells (KNS42 cells). These activating ACVR1 mutations were exclusively in midline high grade astrocytomas (P = 0.0040, Fisher's exact test).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2149" ], "proposition": "#/proposition/civic.proposition:fVMf9yXRjEnfSFLW1GujuTQeTpPSRsiZ", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:528": { "id": "civic.eid:528", "type": "Statement", "description": "A randomized clinical trial of 469 patients with previously untreated, HER2-positive, metastatic breast cancer demonstrated improved time to disease progression, objective response rate, and duration of response for patients who received trastuzumab in addition to chemotherapy compared to chemotherapy alone.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:328" ], "proposition": "#/proposition/civic.proposition:FonbMwrb-ED595aPspkqm9KmG4hPUrLR", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:529": { "id": "civic.eid:529", "type": "Statement", "description": "A randomized clinical trial of 186 patients with previously untreated, HER2-positive, metastatic breast cancer demonstrated improved overall survival, response rate, response duration, time to progression, and time to treatment failure for patients who received trastuzumab in addition to chemotherapy (docetaxel) compared to chemotherapy alone.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:329" ], "proposition": "#/proposition/civic.proposition:FonbMwrb-ED595aPspkqm9KmG4hPUrLR", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6044": { "id": "civic.eid:6044", "type": "Statement", "description": "In this double-blind, randomized, placebo-controlled, multicentre study, adult patients with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) to receive cobimetinib or placebo, in combination with oral vemurafenib. Progression-free survival was the primary endpoint.\nBetween Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). Investigator-assessed median progression-free survival was 12.3 months for cobimetinib and vemurafenib versus 7.2 months for placebo and vemurafenib (HR 0.58 [95% CI 0.46-0.72], p<0.0001). Median overall survival was 22.3 months for cobimetinib and vemurafenib versus 17.4 months for placebo and vemurafenib (HR 0.70, 95% CI 0.55-0.90; p=0.005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2441" ], "proposition": "#/proposition/civic.proposition:HhM76lXnMmZ848g0soiLrgfhxsZVbL1X", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:6178": { "id": "civic.eid:6178", "type": "Statement", "description": "Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 792 (91%) patients had V600E, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 150/397 patients (38%) in the treatment group and 229/395 patients (58%) in the placebo group for a 95% CI Hazard Ratio of 0.48 (0.39-0.58).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2475" ], "proposition": "#/proposition/civic.proposition:I_7vf1IZYIb8nUrIGtn0YyJ6EGctsiuq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6179": { "id": "civic.eid:6179", "type": "Statement", "description": "Adjuvant dual treatment with BRAF inhibitor dabrafenib and MEK inhibitor trametinib was administered to patients with stage III resected melenoma with V600E or V600K mutation in this stage III trial (COMBO-AD, NCT01682083). 78 (9%) patients had V600K, and were administered dabrafenib and trametinib or placebo for 12 months. In subsequent analysis, relapse or death occurred in 16/41 patients (39%) in the treatment group and 19/37 patients (51%) in the placebo group for a 95% CI Hazard Ratio of 0.54 (0.27-1.06).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2475" ], "proposition": "#/proposition/civic.proposition:g0fd3ewNtFwEkLnmURdV7KmWlFC99c85", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6469": { "id": "civic.eid:6469", "type": "Statement", "description": "In this study, the authors analyzed 53 cases of giant cell tumour of bone using capillary sequencing and massively parallel sequencing. They identified histone 3.3 mutations in 49/53 cases (92%). All variants were located in the H3F3A gene and involved substitutions at glycine 34, comprising 48 G34W mutations and 1 G34L mutation.\nThe authors additionally screened 268 other bone and cartilage tumours for mutations in H3F3A and H3F3B. G34W mutations were not identified in these other tumour types, although one osteosarcoma harboured a G34R variant.\nThe study states that histone 3.3 mutations show tumour-type specificity and notes that these findings may have diagnostic utility, particularly in cases where tumour classification is uncertain.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2570" ], "proposition": "#/proposition/civic.proposition:-MdUpj4yA4RiqdNFc2aB-8Taf_UAmXwN", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6938": { "id": "civic.eid:6938", "type": "Statement", "description": "In this Phase III trial (NCT01584648 COMBI-d), previously untreated patients with unresectable stage IIIC or IV melanoma with BRAF V600E (359 patients) or V600K (61 patients) received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival and secondary endpoints including disease response. The hazard ratio for progression or death in the V600E group was 0.81 for dabrafenib-trametinib vs dabrafenib-alone. Of 179 V600E patients in the dabrafenib-trametinib group, 68% of patients had a response, which was 15 percentage points higher than in the dabrafenib-alone group (95% CI, 4 to 24; P=0.006).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2671" ], "proposition": "#/proposition/civic.proposition:I_7vf1IZYIb8nUrIGtn0YyJ6EGctsiuq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6939": { "id": "civic.eid:6939", "type": "Statement", "description": "In this Phase III trial (NCT01584648 COMBI-d), previously untreated patients with unrescectable stage IIIC or IV melanoma with BRAF V600E (359 patients) or V600K (61 patients) received dabrafenib and trametinib or dabrafenib alone with primary endpoint of progression free survival and secondary endpoints including disease response.\n\nIn the V600K group hazard ratio for progression or death was 0.68; 95% confidence interval for dabrafenib\u2013trametinib vs. dabrafenib alone.\n\nOf 31 patients in the V600K dabrafenib + trametinib group, 61% of patients had a response, which was 21 percentage points higher than in the V600K dabrafenib monotherapy group. (95% CI, -3 to 46; P=0.1)", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2671" ], "proposition": "#/proposition/civic.proposition:g0fd3ewNtFwEkLnmURdV7KmWlFC99c85", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6940": { "id": "civic.eid:6940", "type": "Statement", "description": "In this Phase I and II study (NCT01072175) patients with metastatic melanoma were given dabrafenib and trametinib combination therapy vs. dabrafenib monotherapy. From V600E patients, 45 received monotherapy and 92 received combination therapy. Hazard ratio for progression or death was 0.43 (95% CI, 0.27-0.71). Both patients with the BRAF V600E and V600K mutation showed significant improvement in progression-free survival.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:103" ], "proposition": "#/proposition/civic.proposition:I_7vf1IZYIb8nUrIGtn0YyJ6EGctsiuq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6941": { "id": "civic.eid:6941", "type": "Statement", "description": "In this Phase I and II study (NCT01072175), patients with metastatic melanoma were treated with either a combination of dabrafenib and trametinib or dabrafenib monotherapy. Among patients with the V600K mutation, 9 received monotherapy and 16 received combination therapy.\nThe hazard ratio for progression or death was 0.19 (95% CI, 0.05\u20130.66). Overall, patients with BRAF V600E or V600K mutations showed significant improvement in progression-free survival.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:103" ], "proposition": "#/proposition/civic.proposition:g0fd3ewNtFwEkLnmURdV7KmWlFC99c85", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6955": { "id": "civic.eid:6955", "type": "Statement", "description": "In a study sequencing 61 patients (median age 6.3) with diffuse intrinsic pontine glioma (DIPG), 12 variants affecting ACVR1 were observed. Five patients had G328V within the kinase domain. The ACVR1 G328V mutation was expressed using the pCDH511b vector in immortalized normal human astrocytes (iNHAs) where it activated downstream BMP signaling and enhanced cell growth. Activating ACVR1 mutations are recurrent and support diagnosis of high grade glioma. PEDIATRIC", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2680" ], "proposition": "#/proposition/civic.proposition:H6qvcvpF_jzQmVg72PCxDbwJIAsMh58Q", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6965": { "id": "civic.eid:6965", "type": "Statement", "description": "In this Phase III trial (coBRIM, NCT01689519) of 495 V600 mutant melanoma patients, 56 had V600K mutation. 32 patients were treated with vemurafenib and placebo, and 24 were treated with vemurafenib and cobimetinib and tested for progression free survival. 17 of 32 monotherapy group patients had an event with median progression free survival of 5.3 months. In the combination group 4 of 24 patients had an event with median progression-free survival not met, however, when in combination with other V600 mutations median progression-free survival was 9.9 months with combination treatment. Median time to followup for the whole cohort was 7.3 months. Hazard Ratio for progression or death was 0.27 (0.09-0.81).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:963" ], "proposition": "#/proposition/civic.proposition:g0fd3ewNtFwEkLnmURdV7KmWlFC99c85", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6966": { "id": "civic.eid:6966", "type": "Statement", "description": "In this Phase 1b study, 129 patients with unresectable or metastatic melanoma were verified for BRAF V600 mutation using the cobas 4800 mutation test were selected who had progressed on vemurafenib (66 patients) or never received BRAF inhibitor (63 patients). The combination of vemurafenib and cobimetinib was deemed safe and tolerable. Confirmed objective responses were seen in 15% of vemurafenib progressed patients and median progression-free survival was 2.8 months (95% CI 2\u00b76\u20133\u00b74). Confirmed objective responses were seen in 87% of patients who had never received BRAF inhibitor, including 10% with complete response. Median progression-free survival was 13.7 months (95% CI 10\u00b71\u201317\u00b75). The majority of patients had BRAF V600E mutation. Post-hoc sequencing of 94 tumor samples indicated seven tumors with a mutation other than BRAF V600E.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2688" ], "proposition": "#/proposition/civic.proposition:HhM76lXnMmZ848g0soiLrgfhxsZVbL1X", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7156": { "id": "civic.eid:7156", "type": "Statement", "description": "Patients with completely resected colorectal adenocarcinoma (Stage II-III) were treated with fluorouracil and leucovorin +/- ironotecan. Of the 1,307 FFPE samples tested, V600E was observed in 31 Stage II samples (7.6%) and 72 Stage III samples (7.9%). V600E was prognostic for overall survival, but not for relapse-free survival, in patients with stages II and III combined, and in stage III alone. For all MSI low and stable tumors, BRAF V600E positive samples had a hazard ratio (HR) of 2.19 (95% CI, 1.43 to 3.37, P=0.00034). For all samples in the cohort (MSI-H and MSI-L) BRAF V600E positive samples had a 1.66 HR (95% CI, 1.15 to 2.40, P=0.0069). The authors note prognostic value for BRAF V600E, especially in non-MSI high tumors. The authors present this as a prognostic result for BRAF V600E in the patent population, but also note that the patient population was all given standard chemotherapy.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2783" ], "proposition": "#/proposition/civic.proposition:sXFJwmFRv74A8_wLpTiNttPaZo_dDR52", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7157": { "id": "civic.eid:7157", "type": "Statement", "description": "The CRYSTAL Phase III Trial evaluated efficacy of irinotecan, fluorouracil, and leucovorin (FOLFIRI) with or without Cetuximab for colorectal cancer patients who presented with unresectable metastatic disease. BRAF mutation status (V600E) was analyzed via LightMix BRAF V600E Kit. V600E mutations were detected in 60/999 tumor samples (6%), 59 of which were wild-type for KRAS. When comparing patients with wildtype KRAS (n=625), BRAF V600E tumors had worse outcomes relative to BRAF wildtype. For patients with BRAF V600E tumors (n=566), median overall survival (OS) was 25.1 months with cetuximab and 21.6 months without cetuximab. For patients with wildtype BRAF (n=59), median OS was 14.1 months with cetuximab and 10.3 months without cetuximab.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:1931" ], "proposition": "#/proposition/civic.proposition:sXFJwmFRv74A8_wLpTiNttPaZo_dDR52", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7158": { "id": "civic.eid:7158", "type": "Statement", "description": "In the Medical Research Council (MRC) COIN trial, ISRCTN27286448, patients who presented with advanced colorectal cancer were randomly assigned to chemotherapy (oxaliplatin and fluoropyrimidine; arm A), or chemotherapy plus cetuximab (arm B). Median overall survival was found to differ by mutation, regardless of treatment. Median overall survival was 8.8 months (IQR 4.5-27) for patients with BRAF variants, 14.4 months (IQR 8.5-24.0) for patients with KRAS variants, and 20.1 months (IQR 11.5-31.7) for wildtype patients. BRAF mutations were found in 102/1291 samples (7.90%), and of these, 12 were D594G and 90 V600E.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2784" ], "proposition": "#/proposition/civic.proposition:Ee5MeJ8FVGt1eH6YyUbSagII2B47EETC", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7159": { "id": "civic.eid:7159", "type": "Statement", "description": "A meta analysis was performed using data from 21 published studies (n = 9885 patients) to assess prognostic value of BRAF mutations in colorectal cancer. When evaluating 14 studies (n = 7778 patients), the odds ratio (OR) of a proximal lesion, which is associated with greater mortality in colon cancer, was increased for patients with BRAF mutations (OR 5.222, 95% CI 3.801\u20137.174, P < 0.001). When evaluating 4 studies (n = 1526 patients), the odds ratio of T4 tumors, which indicates tumor growth past bowel lining, was increased for patients with BRAF mutations (OR 1.761, 95% CI 1.164\u20132.663, P = 0.007). When evaluating 8 studies (n = 2786 patients), the odds ratio of poor tumor differentiation was increased in patients with BRAF mutations (OR 3.816, 95% CI 2.714\u20135.365, P < 0.001). These results support that BRAF mutations indicate poor prognosis for patients with colorectal cancer.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2785" ], "proposition": "#/proposition/civic.proposition:Ee5MeJ8FVGt1eH6YyUbSagII2B47EETC", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7283": { "id": "civic.eid:7283", "type": "Statement", "description": "In a phase 1/2 trial, patients with refractory or relapsed AML with FLT3 mutation (n=191; ITD n=162, D835 n=13, ITD-D835 n=16) received gilteritinib. 49% (93/191) of patients achieved an overall response, 9% (n=18) complete remission, 5% (n=10) complete remission with incomplete platelet recovery, 22% (n=42) complete remission with incomplete hematological recovery, and 12% (n=23) reached partial remission. The refractory or relapsed AML FLT wildtype group treated with gilteritinib(n=58) had lower overall response rate (12%), complete remission (2%), complete remission with incomplete platelet recovery (0%), complete remission with incomplete hematological recovery (7%), and fewer reached partiral remission (3%). Also, bone marrow myeloblast reduction was greater in FLT3 mutant patients compared to FLT3 wildtype.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2871" ], "proposition": "#/proposition/civic.proposition:Tsx2GJOXt4UF0YDkD9viIYu59szArQRJ", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7290": { "id": "civic.eid:7290", "type": "Statement", "description": "In a large-scale international study RNA sequencing was performed to delineate the transcriptome landscape of 1,223 B-cell ALL cases. Twenty two cases were found to have P80R misense mutation in the DNA-binding domain of the PAX5 transcription factor gene. The P80R cases had unique expression profile and did not have any other known key driver mutations. The P80R is proposed to define a specific molecular/genetic subtype of B-ALL. \n .", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2875" ], "proposition": "#/proposition/civic.proposition:yvWibePmbsIs6FfPAVx_MwzV3k3mi9EQ", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7291": { "id": "civic.eid:7291", "type": "Statement", "description": "Integrated genomic analysis was performed for 1,988 childhood and adult B-ALL cases. Forty four cases (2.2%) showed the P80R substitution in the DNA binding domain for the PAX5 transcription factor gene. These cases were characterized by a unique expression profile. In the majority of the cases the mutation was hemizygous or homozygous, owing to deletion of the wild-type PAX5 allele or copy-neutral loss of heterozygosity. In 96% (42 of 44) of cases, the PAK5 P80R was accompanied by RAS and/or JAK-STAT signaling-pathway alterations (such as NRAS, KRAS, PTPN11, NF1, IL7R), thereby suggesting cooperativity between deregulated PAX5 activity and kinase signaling. The PAX5 P80R is proposed to define a distinct subtype of B-ALL.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2876" ], "proposition": "#/proposition/civic.proposition:vZ_QG5pVMawoRBEDEbRnllVJSZj5UeMX", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:7465": { "id": "civic.eid:7465", "type": "Statement", "description": "In in vitro studies, COS-7 cells transfected with KIT D816V mutant and TF-1 cells expressing KIT D816V were treated with imatinib (1 and 10 \u00b5M), and phosphorylation of the receptor was evaluated by western blotting; no reduction in phospho-KIT signal was observed following treatment.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2054" ], "proposition": "#/proposition/civic.proposition:ZNvdUmZEVR7Ihz5Vy4iHnVvB5dEvMn_D", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:8106": { "id": "civic.eid:8106", "type": "Statement", "description": "Gilteritinib inhibited the cell growth of Ba/F3 cells expressing D835Y (IC50 1.6 nM; 95% CI: 1.1\u20132.4 nM) compared to controls (IC50 420nM; 95% CI: 350\u2013500 nM). Additionally, immunoblots showed gliteritinib reduced phosphorylation of FLT3 and downstream targets in Ba/F3 D835Y cells in a dose dependent manner. Furthermore, in nude mice xenografted with Ba/F3 cells expressing D835Y, gilteritinib showed antitumor efficacy at 10 mg/kg and 30 mg/kg, and induced tumor regression at 30 mg/k. Computational modelling demonstrated that gilteritinib interacts with activated FLT3 at the ATP-binding site, which is distant from the D835 containing activation loop. This inhibitory mechanism allows for kinase inhibition to occur in the face of D835 mutation.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3332" ], "proposition": "#/proposition/civic.proposition:ixYgVVoBgYTq8c-mSnrBcWvwQ1UV5MPX", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:8108": { "id": "civic.eid:8108", "type": "Statement", "description": "A 35 year-old male patient (AML4) presented with a FLT3-ITD mutation at diagnosis and was refractory to induction and salvage chemotherapy. He then received quizartinib and underwent allogenic transplant, but relapsed after 6 months. He then responded to sorafenib, but had disease progression with a FLT3-D835Y mutation. The patient derived relapse sample containing ITD and D835Y mutations was sensitive to gilteritinib based on cytotoxicity assays using MTT. Additionally, immunoblot demonstrated gilteritinib reduced FLT3 phosphorylation in Ba/F3 cells expressing only D835Y with an IC50 of 1.4 nM.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3336" ], "proposition": "#/proposition/civic.proposition:nrOXBqSxt0tK0bH3g3YTVxFGhLEcRRl2", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:8193": { "id": "civic.eid:8193", "type": "Statement", "description": "This study evaluated forty-nine cases of rhabdomyosarcoma (RMS) (17 cases of alveolar RMS, 10 of embryonal RMS, 21 of spindle cell and sclerosing RMS, and a single case of a pleomorphic RMS) for MYOD1 (L122R), PIK3CA (H1047), and PIK3CA (E542/E545) variants. All 10 cases that were positive for the MYOD1 (L122R) variant were either the spindle cell (3/12) or the sclerosing (7/9) subtypes of RMS, while all 10 cases of the embryonal subtype of RMS were negative for the MYOD1 (L122R) variant. The study suggests that the MYOD1 L122R variant is specific for spindle cell and sclerosing subtype of RMS (where it was detected in 10/21 cases or 48%). The study also confirmed the positive relationship between the spindle cell and the sclerosing subtypes of RMS, which both can have the same molecular abnormality (MYOD1 L122R variant) and are now considered to be the same subtype. Finally, the study confirmed the negative correlation between the aforementioned subtypes with the embryonal subtype of rhabdomyosarcoma.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3378" ], "proposition": "#/proposition/civic.proposition:Gi-v-zsAXk2UUOJTcrewplxEw1u6KDls", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:8351": { "id": "civic.eid:8351", "type": "Statement", "description": "A 62-year-old female patient (AML5) was refractory to conventional chemotherapy and developed disease progression to quizartinib due to a D835I mutation. Using MTT to measure cytotoxicity, gilteritinib inhibited this patient\u2019s relapse sample. Additionally, immunoblot demonstrated gilteritinib inhibited FLT3 phosphoryaltion at a concentration of 20 nM in the patient dereivd relapse cells.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3336" ], "proposition": "#/proposition/civic.proposition:smPrVK1rHT1OYFe7KxZoHBxwNBZxsq57", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:8360": { "id": "civic.eid:8360", "type": "Statement", "description": "In an in vitro kinase experiment, kinases wtih the KIT D816V mutation demonstrated resistance to imatinib (IC50: >10,000nM vs. 1550nM) treatment compared to the KIT wild-type kinase. In the HMC-1 human cell line, KIT V560G+, D816V+ mutants treated with imatinib did not show reduced levels of phospho-KIT, growth inhibition, or Annexin V binding at any concentration of treatment. In an ex vivo experiment using primary bone marrow cells from four mastocytosis patients harboring the KIT D816V mutation, imatinib was not effective in reducing mast-cell percentage when compared to no treatment.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2060" ], "proposition": "#/proposition/civic.proposition:UWdN7VNwP7OctYYwjoM_2jejFvJe1rFv", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:863": { "id": "civic.eid:863", "type": "Statement", "description": "This prospective study enrolled 31 Enzalutamide-treated (group 1) and 31 Abiraterone-treated (group 2) patients with metastatic castration-resistant prostate cancers (CRPC). AR-V7 variant was detected by RT-PCR in circulating tumor cells in 39% (group 1) and 19% (group 2). AR-V7+ patients in both groups had lower prostate-specific antigen (PSA) response rate (0% vs. 68%; p=0.004) and shorter PFS (median, 1.3 months vs not reached, p<0.001) and OS (median, 10.6 months vs. not reached, p=0.006) compared to AR-V7- patients. The authors conclude that detection of AR-V7 in circulating tumor DNA from CRPC patients is associated with poor outcome and treatment resistance.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:578" ], "proposition": "#/proposition/civic.proposition:1BDhq1S3vZeLI6hJCpBdkuYa1wW46dpq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:879": { "id": "civic.eid:879", "type": "Statement", "description": "A phase III clinical trial (NCT00949650) found that median progression free survival among patients with exon 19 deletions or L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = 0.001).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:592" ], "proposition": "#/proposition/civic.proposition:lNNbf8EKUZAdgxKA2qni4mLglRkfgTjA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:883": { "id": "civic.eid:883", "type": "Statement", "description": "In a phase 2 study of patients with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) and EGFR mutations, treated with afatinib were assessed by objective response. 129 patients were treated with afatinib. 66% of the 106 patients with two common activating EGFR mutations (deletion 19 or L858R) had an objective response compared to 39% of 23 patients with less common mutations.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:594" ], "proposition": "#/proposition/civic.proposition:lNNbf8EKUZAdgxKA2qni4mLglRkfgTjA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:885": { "id": "civic.eid:885", "type": "Statement", "description": "A randomized phase 3 trial (NCT00446225) involving 173 NSCLC patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease. Patients were randomly allocated (1:1) to receive either erlotinib or standard chemotherapy. The primary endpoint was progression-free survival (PFS). Median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:595" ], "proposition": "#/proposition/civic.proposition:mCQYLirVeuIXrHZ2ElPCxdxLKC24cz_-", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:8851": { "id": "civic.eid:8851", "type": "Statement", "description": "In this international phase 1/2 trial (NCT03157128), 55 RET-mutant medullary thyroid cancer patients who had previously received the multi-kinase inhibitors vandetanib and/or cabozantinib received the highly selective RET-inhibitor selpercatinib. Response in this previously treated population was 69% (95% CI, 55 to 81) with 5 complete responses (CR) and 33 partial responses (PR). The 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the response rate was 73% (95% CI, 62 to 82) with 10 CR and 54 PR. The 1-year progression-free survival was 92% (95% CI, 82 to 97). The most frequent RET mutations overall included RET M918T (57%)in the kinase domain, RET mutations in extracellular cysteines residues at positions 609, 611, 618, 620, 630, and 634 (19%), and the RET V804M/L (7.6%) gatekeeper mutation. Responses were seen across all qualifying RET mutations including the V804M/L gatekeeper which is an acquired resistance mechanism seen with vandetanib and cabozantinib treatment.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3693" ], "proposition": "#/proposition/civic.proposition:WX86xPJioCbnH8-kbfM6EmP0be5CxQoB", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Validated association", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "A" }, "mappings": [ { "coding": { "name": "authoritative evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000001" }, "relation": "exactMatch" } ] } }, "civic.eid:8923": { "id": "civic.eid:8923", "type": "Statement", "description": "This study was designed to test the efficacy of FLT3 inhibitors in vitro against FLT3-ITD and other TKD variants clinically observed. IC50s were determined from immunoblots quantifying FLT3 phosphorylation in endogenous (Molm14) or ectopic expression FLT3-ITD cell lines (TF-1, Ba/F3) and the endogenous wildtype FLT3 SEMK2 cell line after gilteritinib treatment. IC50 values ranged from 1.4 to 1.8 nM in the three FLT3-ITD lines compared to 5nM in wildtype cells, suggesting increased sensitivity to the inhibitor. As measured by MTT assay, primary cultures from two AML patients with high allelic FLT3-ITD showed cytotoxic response to gilteritinib. Additionally, plasma taken from 3 patients receiving 120mg of gilteritinib daily was able to inhibit FLT3 phosphorylation in Molm14 cells.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3336" ], "proposition": "#/proposition/civic.proposition:13pQSub9TfI2E2_x3lQaV9W4vsofZMLN", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:8924": { "id": "civic.eid:8924", "type": "Statement", "description": "In vitro gilteritinib treatment of MV4-11 and MOLM-13 cells, which endogenously express FLT3-ITD, showed growth suppression based on CellTiter GLO cytotoxicity assays with IC50 values of 0.92 nM (95% CI: 0.23\u20133.6 nM) and 2.9 nM (95% CI: 1.4\u20135.8 nM), respectively. Phosphorylation of FLT3 and its downstream targets were rapidly inhibited in MV4-11 cells relative to control treatment (DMSO). In a mouse xenograft model using MV4-11 cells, increasing doses of gilteritinib further reduced tumor size and growth and inhibited phosphorylation of both FLT3 and STAT5 (N=6, p<0.05 at lowest dose). Gilteritinib inhibited growth in vitro of Ba/F3 cells expressing FLT3-ITD (IC50 1.8nM; 95% CI: 1.0-3.0 nM) and in vivo as tumor maintenance or shrinkage was also significant in mice xenografted with Ba/F3 FLT3-ITD cells (N=5, p<0.001). Mice receiving an intra-bone marrow injection of MV4-11 cells labelled with luciferase began gilteritinib treatment on day 15. Gilteritinib treated mice showed significantly less widespread disease at day 42 than control counterparts (N=10, p<0.001) and significantly improved survival (log-rank, p<0.001).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:3332" ], "proposition": "#/proposition/civic.proposition:13pQSub9TfI2E2_x3lQaV9W4vsofZMLN", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:9547": { "id": "civic.eid:9547", "type": "Statement", "description": "This multicenter clinical trial study (PROPHECY) enrolled 118 patients with metastatic castration-resistant prostate cancers (CRPC) on Abiraterone or Enzalutamide treatment. The Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay were used to detect AR-V7 variants. The authors demonstrated that detection of this variant is independently associated with poor PFS and OS in patients treated with Abiraterone or Enzalutamide suggesting that alternative treatment options should be offered when AR-V7 is detected.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:4082" ], "proposition": "#/proposition/civic.proposition:1BDhq1S3vZeLI6hJCpBdkuYa1wW46dpq", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:963": { "id": "civic.eid:963", "type": "Statement", "description": "Cell line, xenograft, and transgenic models were used to establish Osimertinib as an inhibitor of both EGFR mutation sensitizing (L858M, del exon 19) and T790M resistance mutants. Preclinically, the drug inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines. Sustained tumor regression was observed in EGFR-mutant tumor xenograft and transgenic models. Treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC was reported as proof of principle.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:665" ], "proposition": "#/proposition/civic.proposition:MzXNEXAgp9_wIjD84MT_eEV7b0n_4HG0", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:965": { "id": "civic.eid:965", "type": "Statement", "description": "This phase I/II trial (NCT01802632) involved 253 non-small cell lung cancer patients with activating EGFR mutations, who had progressed on first generation tyrosine kinase inhibitor treatment, and were subsequently treated with Osimertinib (AZD9291). The overall objective tumor response rate was 51%. Among 127 patients with EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without EGFR T790M, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months in EGFR T790M-positive patients and 2.8 months in EGFR T790M-negative patients.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:667" ], "proposition": "#/proposition/civic.proposition:MzXNEXAgp9_wIjD84MT_eEV7b0n_4HG0", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:966": { "id": "civic.eid:966", "type": "Statement", "description": "This study summarized 9 EGFR-mutant patients from two clinical trials involving rociletinib (NCT01526928) and subsequent osimertinib (NCT01802632). 8 were T790M-positive prior to treatment with osimertinib. 6 transitioned directly from rociletinib to osimertinib. 3 patients achieved PR and 4 achieved SD. The median PFS was 208 days (95% CI, 41-208 days). Among 6 patients who transitioned directly from rociletinib to osimertinib all derived clinical benefit from osimertinib with either prolonged SD or PR.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:668" ], "proposition": "#/proposition/civic.proposition:MzXNEXAgp9_wIjD84MT_eEV7b0n_4HG0", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:967": { "id": "civic.eid:967", "type": "Statement", "description": "For cells harboring EGFR T790M mutation, osimertinib and rociletinib showed potent inhibition compared to erlotinib or afatinib. This study performed drug response assays using five human NSCLC cell lines, two of which contained T790M mutations (PC-9ER, H1975). In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:669" ], "proposition": "#/proposition/civic.proposition:Jo0OwkHV2-KqaiORVZsOo2YHpeFhfjW2", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:968": { "id": "civic.eid:968", "type": "Statement", "description": "Cells harboring L858R were sensitive to afatinib. This study performed drug response assays using five human NSCLC cell lines with various combinations of EGFR mutations. In order to directly compare the sensitivity of multiple EGFR mutations to EGFR-TKIs the authors also generated multiple EGFR transduced Ba/F3 stable cell lines and evaluated sensitivity to EGFR-TKIs by MTS assay.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:669" ], "proposition": "#/proposition/civic.proposition:3n7vu1vTbv9cSmlyrCq4fNuh_5YNzo1c", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Preclinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "D" }, "mappings": [ { "coding": { "name": "preclinical evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000009" }, "relation": "exactMatch" } ] } }, "civic.eid:982": { "id": "civic.eid:982", "type": "Statement", "description": "Afatinib is an irreversible covalent inhibitor of EGFR (second generation). This Phase III clinical trial (LUX-Lung 6; NCT01121393) was performed in Asian patients with EGFR mutant advanced NSCLC. 364 eligible patients with EGFR mutations were assigned to afatinib (n=242) or gemcitabine and cisplatin (n=122) treatment. The trial observed significantly longer median progression-free survival with afatinib vs. gemcitabine and cisplatin treatment (11.0 vs. 5.6 months). Afatinib/Chemotherapy group compositions: 51.2/50.8 % del 19; 38/37.7 % Leu858Arg; 10.8/11.5 % Uncommon.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:679" ], "proposition": "#/proposition/civic.proposition:lNNbf8EKUZAdgxKA2qni4mLglRkfgTjA", "direction": "supports", "strength": { "type": "MappableConcept", "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } } }, "assertion": { "civic.aid:10": { "id": "civic.aid:10", "type": "Statement", "description": "Vemurafenib and cobimetinib combination is an FDA approved first line treatment for BRAF V600E mutant metastatic melanoma based on clinical data including the Phase III coBRIM trial. The cobas 4800 BRAF V600 Mutation Test is approved as an FDA companion test for Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/10" ], "proposition": "#/proposition/civic.proposition:yIxQ2zvDhwzUh5UGOy90mmnnkbxU3a3z", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/6044", "https://civicdb.org/links/evidence/1421", "https://civicdb.org/links/evidence/6966" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:iS8NTzApX0dHrxVCjn1V2Vn_GaU6sUcB", "hasEvidenceItems": [ "#/evidence/civic.eid:6044", "#/evidence/civic.eid:1421", "#/evidence/civic.eid:6966" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:105": { "id": "civic.aid:105", "type": "Statement", "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor gefitinib is associated with improved progression free survival over chemotherapy in EGFR L858R patients.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/105" ], "proposition": "#/proposition/civic.proposition:s1e8HpFqnVZBo4v3NGTHJG5WJ-5QSZ31", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11241", "https://civicdb.org/links/evidence/2621", "https://civicdb.org/links/evidence/229", "https://civicdb.org/links/evidence/1665", "https://civicdb.org/links/evidence/2634", "https://civicdb.org/links/evidence/276", "https://civicdb.org/links/evidence/3811" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:IAd8IXLDyxX3SeXoMU9ephk7bmyIgfXA", "hasEvidenceItems": [ "#/evidence/civic.eid:2621", "#/evidence/civic.eid:229", "#/evidence/civic.eid:1665", "#/evidence/civic.eid:2634", "#/evidence/civic.eid:276", "#/evidence/civic.eid:3811" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:11": { "id": "civic.aid:11", "type": "Statement", "description": "Vemurafenib and cobimentinb is an FDA approved first line treatment for BRAF V600K mutant metastatic melanoma based on clinical data including the Phase III coBRIM trial. The cobas 4800 BRAF V600 Mutation Test is approved as an FDA companion test for Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/11" ], "proposition": "#/proposition/civic.proposition:qf6t5IHm3JSitAlUdiz0NmHE4KBwRcbM", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/6044", "https://civicdb.org/links/evidence/6965", "https://civicdb.org/links/evidence/6966" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:avmo6K2HDx0cYoLdy9y_wEYWN6Rqt6xP", "hasEvidenceItems": [ "#/evidence/civic.eid:6044", "#/evidence/civic.eid:6965", "#/evidence/civic.eid:6966" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:113": { "id": "civic.aid:113", "type": "Statement", "description": "Angiocentric glioma is a rare, CNS WHO grade 1 glioma with a diffuse growth pattern and a focal angiocentricity. Almost all angiocentric gliomas have a MYB::QKI gene fusion, and the remainder generally have another MYB alteration. MYB is a transcription factor that is upregulated when structural rearrangements result in truncation of its C-terminal negative-regulatory domain. Professional guidelines (WHO) list the presence of a MYB alteration or a DNA methylation profile meeting the appropriate calibrated score thresholds for diffuse glioma, MYB- or MYBL1-altered as desirable diagnostic criteria for angiocentric glioma (WHO classification of tumours series, 5th ed.; vol. 7).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/113" ], "proposition": "#/proposition/civic.proposition:MtrD2SDgsSSrj4RHPHm96JfvcSJGnuE7", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11773", "https://civicdb.org/links/evidence/11769", "https://civicdb.org/links/evidence/11774", "https://civicdb.org/links/evidence/11775" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:ySWkfWNF5trt_6TpSo-cxC0l5JdAF7vd", "hasEvidenceItems": [ "#/evidence/civic.eid:11774", "#/evidence/civic.eid:11775" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:114": { "id": "civic.aid:114", "type": "Statement", "description": "Diffuse astrocytoma, MYB- or MYBL1-altered, is a rare, CNS WHO grade 1, diffusely infiltrative astroglial neoplasm with genetic alterations in MYB or MYBL1 associated with epileptic seizures in children and adults. MYB and MYBL1 are closely related transcriptional transactivators that become upregulated when structural rearrangements result in truncation of their C-terminal negative-regulatory domain. Professional guidelines (WHO) list the presence of a structural MYB or MYBL1 variant or a DNA methylation profile meeting the appropriate calibrated score thresholds for diffuse astrocytoma, MYB- or MYBL1-altered as essential diagnostic criteria for diffuse astrocytoma, MYB- or MYBL1-altered (WHO classification of tumours series, 5th ed.; vol. 7).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/114" ], "proposition": "#/proposition/civic.proposition:hWhCfYZBbu-0DSy42NaZMwRyHyGHSZL0", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11777", "https://civicdb.org/links/evidence/11778", "https://civicdb.org/links/evidence/11776", "https://civicdb.org/links/evidence/11790" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:dzTHCom0Rs3wi9PR9BQYtS5giwyJ_gg9", "hasEvidenceItems": [ "#/evidence/civic.eid:11777", "#/evidence/civic.eid:11778", "#/evidence/civic.eid:11776", "#/evidence/civic.eid:11790" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:115": { "id": "civic.aid:115", "type": "Statement", "description": "Diffuse astrocytoma, MYB- or MYBL1-altered is a rare, CNS WHO grade 1, diffusely infiltrative astroglial neoplasm with genetic alterations in MYB or MYBL1 associated with epileptic seizures in children and adults. MYB and MYBL1 are closely related transcriptional transactivators that become upregulated when structural rearrangements result in truncation of the C-terminal negative-regulatory domain. Professional guidelines (WHO) list the presence of a structural MYB or MYBL1 variant or a DNA methylation profile meeting the appropriate calibrated score thresholds for diffuse astrocytoma, MYB- or MYBL1-altered as essential diagnostic criteria for diffuse astrocytoma, MYB- or MYBL1-altered (WHO classification of tumours series, 5th ed.; vol. 7).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/115" ], "proposition": "#/proposition/civic.proposition:XrJzaXH29WgjqNsY26KkFWKylWX3aOfv", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11780", "https://civicdb.org/links/evidence/11781", "https://civicdb.org/links/evidence/11779" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:-eeXkrO__QKfMJucX4t58cmySleXZivG", "hasEvidenceItems": [ "#/evidence/civic.eid:11780", "#/evidence/civic.eid:11781", "#/evidence/civic.eid:11779" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:13": { "id": "civic.aid:13", "type": "Statement", "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with the less common BRAF V600K mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. This treatment combination was FDA approved based on the (COMBI-v) trial, where 68 V600K metastatic melanoma patients had either a 65 percent response rate to dabrafenib and trametinib combination therapy, or a 44 percent with vemurafenib alone (civic.EID:4181), as well as the COMBI-D (civic.EID:6939), and COMBI-AD (civic.EID:6179) Trials, which also showed superiority of combination therapy.", "extensions": [ { "name": "clinvarAccession", "value": "SCV007542592" } ], "specifiedBy": "#/method/civic.method:2019", "contributions": [ { "type": "Contribution", "extensions": [ { "name": "clinvarAccession", "value": "SCV007542592" } ], "contributor": "#/organization/civic.organization:1", "activityType": "approval.last_reviewed", "date": "2026-04-22" } ], "reportedIn": [ "https://civicdb.org/links/assertion/13" ], "proposition": "#/proposition/civic.proposition:qf6t5IHm3JSitAlUdiz0NmHE4KBwRcbM", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/6179", "https://civicdb.org/links/evidence/6941", "https://civicdb.org/links/evidence/4181", "https://civicdb.org/links/evidence/6939" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:g0fd3ewNtFwEkLnmURdV7KmWlFC99c85", "hasEvidenceItems": [ "#/evidence/civic.eid:6179", "#/evidence/civic.eid:6941", "#/evidence/civic.eid:4181", "#/evidence/civic.eid:6939" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:130": { "id": "civic.aid:130", "type": "Statement", "description": "The EGFR T790M mutation occurs in approximately 50-60% of EGFR mutated non small cell lung cancer (NSCLC) patients treated with first or second-generation EGFR tyrosine kinase inhibitors (TKIs). The third-generation EGFR TKI osimertinib has been shown to inhibit proliferation signaling and growth in cell line and xenograft models (civic.EID:963) and human cell lines (civic.EID:967) with EGFR T790M. Case study reports indicate benefit from osimertinib for NSCLC patients with primary sensitizing EGFR mutations who progressed on first line TKI treatment with the emergence of T790M (civic.EID:12946). Osimertinib was given accelerated approval for treatment of T790M positive NSCLC patients who had progressed on previous TKI therapy based on results from a Phase I study showing a 59% objective response rate to osimertinib in these patients (civic.EID:965), and then granted regular approval after the confirmatory phase 3 trial (AURA3) further indicated benefit with a 71 percent overall response rate in T790M patients who had progressed on TKI therapy versus 31 percent response rate with chemotherapy (civic.EID:1867).", "extensions": [ { "name": "clinvarAccession", "value": "SCV007579162" } ], "specifiedBy": "#/method/civic.method:2019", "contributions": [ { "type": "Contribution", "extensions": [ { "name": "clinvarAccession", "value": "SCV007579162" } ], "contributor": "#/organization/civic.organization:1", "activityType": "approval.last_reviewed", "date": "2026-06-30" } ], "reportedIn": [ "https://civicdb.org/links/assertion/130" ], "proposition": "#/proposition/civic.proposition:ccEXSyDdV9yKrd2eb54y8RTKsnTz5gK2", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/1592", "https://civicdb.org/links/evidence/1867", "https://civicdb.org/links/evidence/11598", "https://civicdb.org/links/evidence/11599", "https://civicdb.org/links/evidence/965", "https://civicdb.org/links/evidence/966", "https://civicdb.org/links/evidence/12946", "https://civicdb.org/links/evidence/963", "https://civicdb.org/links/evidence/967" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:MzXNEXAgp9_wIjD84MT_eEV7b0n_4HG0", "hasEvidenceItems": [ "#/evidence/civic.eid:1592", "#/evidence/civic.eid:1867", "#/evidence/civic.eid:965", "#/evidence/civic.eid:966", "#/evidence/civic.eid:963", "#/evidence/civic.eid:967" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:132": { "id": "civic.aid:132", "type": "Statement", "description": "Astroblastoma, MN1-altered is a rare primary CNS tumor characterized by distinctive histological features including astroblastic pseudorosettes and vascular hyalinization, and defined by the presence of MN1 gene rearrangements that predominantly affect children and young adults . MN1 fusions most frequently involve MN1 and BEND2 genes fused in-frame. Professional guidelines (WHO) list MN1 alterations or a DNA methylation profile meeting the appropriate calibrated score thresholds for astroblastoma, MN1-altered as essential diagnostic criteria for astroblastoma, MN1-altered (WHO classification of tumours series, 5th ed.; vol. 7).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/132" ], "proposition": "#/proposition/civic.proposition:HBsboMPEbvp1boB3ehg_KxKsVhat4eBF", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/8510", "https://civicdb.org/links/evidence/12078", "https://civicdb.org/links/evidence/12079", "https://civicdb.org/links/evidence/12077" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:HoPmN0GuQOF_sGHExod4BPFTGjHG5ijD", "hasEvidenceItems": [ "#/evidence/civic.eid:12078", "#/evidence/civic.eid:12079", "#/evidence/civic.eid:12077" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:146": { "id": "civic.aid:146", "type": "Statement", "description": "CEBPA ( CCAAT Enhancer Binding Protein Alpha) mutations are primary oncogenic drivers in 5% of acute myeloid leukemia (AML) cases in children and 5\u201311% of AML cases in adults. Two main types of mutations are typically observed: isolated mutations in the C-terminal DNA-binding basic leucine zipper (bZip) region and biallelic (CEBPA-dm) mutations, where one mutation occurs in the bZip region and the other in the N-terminal transactivation domain. CEBPA bZip and biallelic mutations are essential diagnostic markers that inform risk stratification and guide treatment decisions. Professional guidelines (WHO) list the presence of bi-allelic mutations in CEBPA, or a single mutation located in the bZIP region as diagnostic criteria for AML with CEBPA mutation.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/146" ], "proposition": "#/proposition/civic.proposition:IfFmE6-xkJoUH_sDPG1TJ94JZhGxZ3AH", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12173", "https://civicdb.org/links/evidence/12174", "https://civicdb.org/links/evidence/12200" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:bZtgpyVtvkJDVAoc9KnLPDSVkEoa3El1", "hasEvidenceItems": [ "#/evidence/civic.eid:12173", "#/evidence/civic.eid:12174", "#/evidence/civic.eid:12200" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:161": { "id": "civic.aid:161", "type": "Statement", "description": "SMARCB1 loss of nuclear expression is an essential molecular alteration in cribriform neuroepithelial tumor (CRINET), a rare non-rhabdoid childhood brain cancer with a distinct histological appearance including cribriform strains and ribbons. Loss of SMARCB1 expression is caused by biallelic inactivation through a combination of mechanisms including deletions of chromosome 22q, SMARCB1 sequence mutations or single-gene deletions of either germline or somatic origin, and loss of heterozygosity. Loss of nuclear SMARCB1 is an essential diagnostic criterion for this newly recognized provisional disease entity in the professional guideline (WHO classification of tumor series, 5th ed. vol. 6; 2021). It should be noted that CRINET has an overlapping methylation profile with atypical teratoid / rhabdoid tumor, AT/RT-TYR subtype, and similarly demonstrates tyrosinase immunopositivity. Therefore, its distinction from AT/RT-TYR has not been fully delineated in the current WHO Classification (5th ed. vol. 6; 2021).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/161" ], "proposition": "#/proposition/civic.proposition:Sed3s6PKc-TTI4ezrUUQmsWlllh156hB", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12332", "https://civicdb.org/links/evidence/12327", "https://civicdb.org/links/evidence/12328" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:bLJMTICxLInRH0TKMzg_3vKxgtvcTpu6", "hasEvidenceItems": [ "#/evidence/civic.eid:12332", "#/evidence/civic.eid:12327", "#/evidence/civic.eid:12328" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:167": { "id": "civic.aid:167", "type": "Statement", "description": "The EPOR gene encodes the erythropoietin receptor, a member of the cytokine receptor family. EPOR rearrangements, including insertion of EPOR distal to the enhancer of either IGH or IGK or truncation of the cytoplasmic tail of EPOR result in abnormal EPOR activation and increased downstream JAK/STAT asignaling. These EPOR rearrangements are included in the set of genetic alterations sufficient for diagnosis of B-lymphoblastic leukaemia/lymphoma with BCR::ABL1-like features, an entity associated with a poor treatment response and high relapse rate which accounts for ~5-9% of B-ALL cases. JAK/STAT pathway activation offers Ruxolitinib (JAK1/JAK2 inhibitor) as a treatment option (AALL1521/INCB18424-269) COG AALL1521 phase II clinical trial).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/167" ], "proposition": "#/proposition/civic.proposition:XeMy0SRleFF_PgwFwMrINmCcJE-dqDsU", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12395", "https://civicdb.org/links/evidence/12397", "https://civicdb.org/links/evidence/12393", "https://civicdb.org/links/evidence/12394", "https://civicdb.org/links/evidence/12396" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:keqgR-6oqGEDayKd85K0KXG1KVjsP-Mn", "hasEvidenceItems": [ "#/evidence/civic.eid:12397" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:168": { "id": "civic.aid:168", "type": "Statement", "description": "AML with inv(3)/t(3;3)(q21q26) is a distinct WHO-recognized entity. It is characterized by its aggressive course and poor prognosis. In this subtype of AML, translocation of GATA2 enhancer (located at 3q21) to MECOM (located at 3q26) leads to overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2, and lack of expression of full-length transcript MDS-EVI1. Besides the classical inv(3)/t(3;3)(q21q26) rearrangement, a number of atypical 3q26/MECOM rearrangements with poor treatment response in AML have been reported in literature. Since atypical 3q26 AMLs are difficult to diagnose given their cytogenetic complexity of and heterogeneity, the importance of routine molecular diagnosis to identify this subgroup of AML cases is highlighted. Use of MECOM FISH to identify 3q26/ MECOM rearrangements routinely for AML diagnostics, and quantitative EVI1 and MDS-EVI1 mRNA expression analysis are important to evaluate role of enhancer hijacking in EVI1 deregulation. It is proposed that both atypical 3q26/MECOM and inv(3)/t(3;3)(q21q26) be classified together as a single entity of 3q26 rearranged AMLs.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/168" ], "proposition": "#/proposition/civic.proposition:5QfhodxmgiUTMQh_x85h_ezYHUf7Mx6J", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12399", "https://civicdb.org/links/evidence/12400", "https://civicdb.org/links/evidence/12401" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:4d6_FmFvSdhjgtNUFlejrSOLK72WvN1M", "hasEvidenceItems": [ "#/evidence/civic.eid:12399", "#/evidence/civic.eid:12400", "#/evidence/civic.eid:12401" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:180": { "id": "civic.aid:180", "type": "Statement", "description": "AR-V7 is an alternatively spliced version of the androgen receptor that was identified in LNCaP derivative cell lines which gained the ability to grow in an androgen depleted medium. The AR-V7 isoform consists of the first three exons of AR, along with a cryptic exon in place of exons 4 through 9. This isoform retains the N terminal transactivation domain, and the DNA binding domain of AR, but loses the hinge region and ligand binding domain, which suggests that this isoform has the capacity to transactivate downstream targets even in the absence of ligand. AR-V7 was expressed in androgen independent cell lines, and more frequently occurs in the setting of AR gene amplification. Expression of AR-V7 in androgen dependent cells induced androgen independence, and knockdown of AR-V7 in androgen independent cells inhibited androgen independent growth. AR-V7 shows increased capacity to translocate to the nucleus in an androgen independent manner. AR-V7 isoforms are found in castration-resistant prostate cancer, salivary duct carcinoma and breast carcinoma. AR-V7 is associated with resistance to Abiraterone and Enzalutamide in patients with metastatic prostate cancer.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/180" ], "proposition": "#/proposition/civic.proposition:20yxFDGj7BnWpM2Oq5w3Oyf5vpvNsXau", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/9547", "https://civicdb.org/links/evidence/9553", "https://civicdb.org/links/evidence/9555", "https://civicdb.org/links/evidence/9576", "https://civicdb.org/links/evidence/12463", "https://civicdb.org/links/evidence/12464", "https://civicdb.org/links/evidence/863" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:-Qrcb8k-aTivnt7DzJvLubEjPvTHCzLT", "hasEvidenceItems": [ "#/evidence/civic.eid:9547", "#/evidence/civic.eid:12463", "#/evidence/civic.eid:12464", "#/evidence/civic.eid:863" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:185": { "id": "civic.aid:185", "type": "Statement", "description": "NPM1 mutations are detected in a large subset of acute myeloid leukemia (AML) patients, particularly those with normal cytogenetics. These mutations typically consist of small insertions in the terminal coding exon of NPM1 (NM_002520.7 exon 11; historically refferd to as exon 12), resulting in elongation of the protein, disruption of the C-terminal nucleolar localization signal, and aberrant cytoplasmic localization (NPMc+). Professional guideline (WHO) recognize AML with mutated NPM1 as a distinct diagnostic entity, with the presence of an NPM1 mutation listed as an essential diagnostic criterion and FLT3 mutation status as a key prognostic determinant (WHO classification of tumors series, 5th ed.; vol. 11).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/185" ], "proposition": "#/proposition/civic.proposition:20Wz0fNXbRm4oSHKTEBdup8uEuNw9B9H", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12494", "https://civicdb.org/links/evidence/108", "https://civicdb.org/links/evidence/12495" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:FieV3ZZI2vPPWcQmyJlvN8LRCQQ-4qWW", "hasEvidenceItems": [ "#/evidence/civic.eid:12494", "#/evidence/civic.eid:108", "#/evidence/civic.eid:12495" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:193": { "id": "civic.aid:193", "type": "Statement", "description": "Spindle cell and sclerosing rhabdomyosarcomas harboring MYOD1 p.L122R mutations are a distinct and often aggressive entity that occurs across pediatric and adult age groups. The MYOD1 p.L122R mutation is a recurrent hotspot mutation that serves as a primary oncogenic driver. In a study of 49 rhabdomyosarcoma cases, all 10 cases that were positive for L122R were either spindle cell or sclerosing subtypes of RMS (civic.EID:8193), and L122R is found at high frequencies in these subtypes (civic.EID:11582, civic.EID:11585). Professional guidelines (WHO) list the detection of MYOD1 mutation as a diagnostic criterion for spindle cell/sclerosing rhabdomyosarcoma (WHO Classification of Tumors, 5th Edition; Soft Tissue and Bone Tumors).", "extensions": [ { "name": "clinvarAccession", "value": "SCV007542591" } ], "specifiedBy": "#/method/civic.method:2019", "contributions": [ { "type": "Contribution", "extensions": [ { "name": "clinvarAccession", "value": "SCV007542591" } ], "contributor": "#/organization/civic.organization:1", "activityType": "approval.last_reviewed", "date": "2026-04-22" } ], "reportedIn": [ "https://civicdb.org/links/assertion/193" ], "proposition": "#/proposition/civic.proposition:9YqXe1zkhx7FCw-nFXAlw8wIlHttPIcD", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/8193", "https://civicdb.org/links/evidence/11582", "https://civicdb.org/links/evidence/11585", "https://civicdb.org/links/evidence/11588" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:Gi-v-zsAXk2UUOJTcrewplxEw1u6KDls", "hasEvidenceItems": [ "#/evidence/civic.eid:8193", "#/evidence/civic.eid:11582", "#/evidence/civic.eid:11585", "#/evidence/civic.eid:11588" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:2": { "id": "civic.aid:2", "type": "Statement", "description": "HER2 amplification defines a clinically relevant subtype of breast cancer. HER2 amplification predicts sensitivity to various targeted therapies including the monoclonal antibody Trastuzumab. The use of Trastuzumab, often in combination with chemotherapy and/or endocrine therapy (depending on hormone receptor status), is now standard of care for HER2-positive breast cancer patients.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/2" ], "proposition": "#/proposition/civic.proposition:RfJA8ZfogRIakdO9AFzNoOhLaTJ72I4W", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/1122", "https://civicdb.org/links/evidence/528", "https://civicdb.org/links/evidence/529" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:FonbMwrb-ED595aPspkqm9KmG4hPUrLR", "hasEvidenceItems": [ "#/evidence/civic.eid:1122", "#/evidence/civic.eid:528", "#/evidence/civic.eid:529" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:20": { "id": "civic.aid:20", "type": "Statement", "description": "BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/20" ], "proposition": "#/proposition/civic.proposition:37YOZRKHDb73M3TBaBcm5WIh6HULdvse", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/103", "https://civicdb.org/links/evidence/7156", "https://civicdb.org/links/evidence/7157", "https://civicdb.org/links/evidence/7158", "https://civicdb.org/links/evidence/7159", "https://civicdb.org/links/evidence/1552" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:sXFJwmFRv74A8_wLpTiNttPaZo_dDR52", "hasEvidenceItems": [ "#/evidence/civic.eid:103", "#/evidence/civic.eid:7156", "#/evidence/civic.eid:7157", "#/evidence/civic.eid:7158", "#/evidence/civic.eid:7159", "#/evidence/civic.eid:1552" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:200": { "id": "civic.aid:200", "type": "Statement", "description": "RET M918T occurs in the kinase domain of RET, and is found in both germline and somatic RET mutations in medullary thyroid cancer (civic.EID:12711). M918T induces transformation of cells which are sensitive to treatment by selpercatinib (civic.EID:11867, civic.EID:11876). M918T is the most prevalent RET mutation found in patients enrolled in medullary thyroid cancer trials (civic.EID:8851, civic.EID:12708), and the only RET mutation reported in cancerhotspots V2. Patients with M918T have improved progression free survival when treated with selpercatinib over physician\u2019s choice of vandetanib or cabozantinib (civic.EID:12598). Selpercatinib is approved for use in medullary thyroid cancer patients with RET mutations including M918T over 2 years of age based on the results of phase 1/2 (civic.EID:12056, civic.EID:12708) and LIBRETTO-531 phase 3 trials (civic.EID:12157).", "extensions": [ { "name": "clinvarAccession", "value": "SCV007579163" } ], "specifiedBy": "#/method/civic.method:2019", "contributions": [ { "type": "Contribution", "extensions": [ { "name": "clinvarAccession", "value": "SCV007579163" } ], "contributor": "#/organization/civic.organization:1", "activityType": "approval.last_reviewed", "date": "2026-04-16" } ], "reportedIn": [ "https://civicdb.org/links/assertion/200" ], "proposition": "#/proposition/civic.proposition:ff-o4NXDstGZueNxFwwwzy55BezJzuhM", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12157", "https://civicdb.org/links/evidence/12598", "https://civicdb.org/links/evidence/12708", "https://civicdb.org/links/evidence/8851", "https://civicdb.org/links/evidence/12056", "https://civicdb.org/links/evidence/12711", "https://civicdb.org/links/evidence/11867", "https://civicdb.org/links/evidence/11876" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:5OFjQDRrBBupMmCAUFH3qIKhyjEpsB-9", "hasEvidenceItems": [ "#/evidence/civic.eid:12157", "#/evidence/civic.eid:12598", "#/evidence/civic.eid:8851", "#/evidence/civic.eid:11867", "#/evidence/civic.eid:11876" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:202": { "id": "civic.aid:202", "type": "Statement", "description": "Published sequencing studies have shown that RET mutations are very common in medullary thryoid carcinoma (MTC) and M918T is the most common specific variant, especially in the MEN2B clinical subtype of familial disease (civic.EID:78) but also in sporadic cases(civic.EID:12800). M918T mutations may predict worse outcomes (civic.EID:74). Biochemical and functional characterization demonstrates that the M918T mutation leads to functional activation of RET relative to wild-type through multiple complementary mechanisms, including increased ATP affinity (>10-fold) and complex stability, reduced conformational rigidity, and the promotion of ligand-independent dimerization and autophosphorylation (civic.EID:12805). Exogenous expression has been shown to induce transformation of Ba/F3 cells (civic.EID:11723), and drive colony formation in NIH3T3 cells (civic.EID:12709, OS2). RET M918T occurs in the region of the tyrosine kinase domain which is associated with multiple endocrine neoplasia type 2 B (OM1). RET M918T is predicted to be deleterious (CHASMplus score 0.314 > VECS gene-specific cutoff of 0.22, OP1). Eleven instances of the variant occur in cancerhotspots.org (V2): 6 Thyroid, 4 Adrenal Gland, 1 Breast (OP3). The variant is absent in gnomAD database (v4.1.0, OP4). Together these criteria indicate that M918T is likely oncogenic, with a score of 9.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "contributions": [ { "type": "Contribution", "contributor": "#/organization/civic.organization:1", "activityType": "approval.last_reviewed", "date": "2026-04-16" } ], "reportedIn": [ "https://civicdb.org/links/assertion/202" ], "proposition": "#/proposition/civic.proposition:T3lh47joZC7fHhrx06N1sydNHPqUkmf3", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/74", "https://civicdb.org/links/evidence/12800", "https://civicdb.org/links/evidence/78", "https://civicdb.org/links/evidence/12711", "https://civicdb.org/links/evidence/12805", "https://civicdb.org/links/evidence/11723", "https://civicdb.org/links/evidence/12709" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_domain_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "moderate" } }, "scoreOfEvidenceProvided": 2, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OM1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "in_silico_impact_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP3" } } } ] }, "civic.aid:203": { "id": "civic.aid:203", "type": "Statement", "description": "FGFR1 Amplification is associated with poor clinical outcomes. In a large breast cancer cohort of 503 assessable patients, FGFR1 amplification was observed in 33 cases (6.6%) and was enriched in the more aggressive luminal B subtype, seen in 69.7 percent of amplified versus 32.6 percent in non-amplified tumors. In this study observed outcome differences did not achieve statistical significance, but there was a trend toward poorer distant metastasis-free survival in patients with FGFR1 amplification [HR=2.08; 95% CI 0.98 to 4.39, P=0.05) (civic.eid:12487). A similar association was observed in the H120 and METABRIC study cohorts of ER-positive breast cancer. In H210 FGFR1 amplification was observed in a higher percentage of luminal B (16.3%, N=17/103) vs luminal A (6.6%, N=6/92) cases and conferred a significant hazard ratio for relapse (HR = 1.96, 95% CI 1.031-3/72, P=0.038). In METABRIC (N=635) the percentage of cases with FGFR amplification was higher in luminal B than in luminal A cases (11.1% vs. 5.5%, P=0.001) and the median relapse-free survival was shorter for cases with amplification than for those without (12.2 vs 21.1 years) (civic.eid:12497). In a separate study of 100 metastatic breast cancer patients, FGFR1 amplification was found in 20 percent of the cohort and associated with decreased median overall survival of 32 versus 54 months (log-rank p=0.0018) (civic.eid:12532). A retrospective study of ctDNA samples from the PALOMA-3 trial (N=401) in patients with advanced ER+ breast cancer found that in both univariable and multivariable analyses gain of FGFR1 was associated with poorer progression-free survival in both treatment groups; there was no interaction with treatment randomization (civic.eid:12486).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/203" ], "proposition": "#/proposition/civic.proposition:UBcuxzjPkzuGctMr4yuC6Y_U4jhetD5c", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "potential" } }, "classification": { "type": "MappableConcept", "name": "Tier II", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier ii" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12486", "https://civicdb.org/links/evidence/12497", "https://civicdb.org/links/evidence/12532", "https://civicdb.org/links/evidence/12487" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:jnJVZ7hQOw374mvXkrRm0tawWjM7BCP_", "hasEvidenceItems": [ "#/evidence/civic.eid:12486", "#/evidence/civic.eid:12497", "#/evidence/civic.eid:12487" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "C" } } } ] }, "civic.aid:206": { "id": "civic.aid:206", "type": "Statement", "description": "Giant cell tumor of bone (GCT) is a locally aggressive and rarely metastasizing neoplasm, accounting for approximately 5% of all primary bone tumors. Driver mutations affecting H3F3A at codon p.G34\u2014most commonly p.G34W (also reported as p.G35W)\u2014are highly specific to GCT and are not observed in other bone tumors. These mutations are present in the majority of cases, reported in up to 92% and 96% of GCTs in different studies (civic.EID:6469, civic.EID:12749). H3F3A mutations are restricted to glycine 34 substitutions, with rare variants such as G34L, G34R, and G34M also described. While highly specific, sensitivity may vary depending on the detection method, with lower rates reported using Sanger sequencing (civic.EID:12750). The World Health Organization (WHO) classification of tumours recognizes the detection of H3F3A p.G34W as a diagnostic criterion for GCT (WHO Classification of Tumours, 5th edition, Volume 3: Soft Tissue and Bone Tumours).", "extensions": [ { "name": "clinvarAccession", "value": "SCV007579161" } ], "specifiedBy": "#/method/civic.method:2019", "contributions": [ { "type": "Contribution", "extensions": [ { "name": "clinvarAccession", "value": "SCV007579161" } ], "contributor": "#/organization/civic.organization:1", "activityType": "approval.last_reviewed", "date": "2026-04-24" } ], "reportedIn": [ "https://civicdb.org/links/assertion/206" ], "proposition": "#/proposition/civic.proposition:baVAhXVwYi2ZxVD52-oSQqAqnysfEipT", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/6469", "https://civicdb.org/links/evidence/12749", "https://civicdb.org/links/evidence/12750" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:Yw-qND3OVkBnT7KWmdImTWa2kGdKm1TM", "hasEvidenceItems": [ "#/evidence/civic.eid:6469", "#/evidence/civic.eid:12749", "#/evidence/civic.eid:12750" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:222": { "id": "civic.aid:222", "type": "Statement", "description": "Osteoblastoma and osteoid osteoma are benign bone tumors that predominantly affect adolescents and young adults. Whole-genome sequencing and cytogenetic studies have shown that these tumors are characterized by FOS rearrangements in the majority of cases, with FOSB rearrangements present in a smaller subset (civic.eid:11596, civic.eid:11597, civic.eid:11787). The rearrangements typically retain the 5' end of FOS or FOSB, including the dominant transactivation and bZIP domains, and involve various 3' fusion partners such as ANKH, RUNX2, and others (civic.eid:11596, civic.eid:11787). FOS immunohistochemistry shows strong nuclear expression in nearly all tumors with FOS rearrangements, and FISH can confirm these genetic alterations, aiding in differentiation from more aggressive osteoblastic osteosarcomas (civic.eid:11596, civic.eid:11786, civic.eid:11597). Professional guidelines (WHO) list a FOS or FOSB rearrangement as a diagnostic criterion for osteoblastoma and osteoid osteoma (WHO classification of tumors series, 5th ed.; vol. 7).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/222" ], "proposition": "#/proposition/civic.proposition:0FwsnkGK4SvaE-P9LJNqOUxEIoCErtVJ", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11596", "https://civicdb.org/links/evidence/11786", "https://civicdb.org/links/evidence/11597", "https://civicdb.org/links/evidence/11787" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:OGoMt62A7QOGJOTDNtMniIHIajyWyAn_", "hasEvidenceItems": [ "#/evidence/civic.eid:11596", "#/evidence/civic.eid:11786", "#/evidence/civic.eid:11787" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:233": { "id": "civic.aid:233", "type": "Statement", "description": "HRAS G13R causes increased proliferation (civic.EID:12906, OS2), increased pERK/ERK ratio and increased GTP-bound HRAS (civic.EID:12905, OS2). This variant count in cancerhotspots.org (V2) is 22 with 50 samples with a somatic variant at the same amino acid position (OS3). The variant is absent in gnomAD database (v4.1.0, OP4). Both OS2 and OS3 criteria are satisfied at full strength (OP1). Together these criteria indicate that G13R is oncogenic, with a score of 10. Variant classification is done using ClinGen MAPK/ERK pathway sc-VCEP guidelines.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/233" ], "proposition": "#/proposition/civic.proposition:LW_4_yJOHxW9zRJVy5Dub4H0i4Gbk9R7", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "definitive" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12905", "https://civicdb.org/links/evidence/12906" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "in_silico_impact_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP1" } } } ] }, "civic.aid:234": { "id": "civic.aid:234", "type": "Statement", "description": "IDH1 R132L is a somatic missense mutation at codon 132 that is expected to confer neomorphic IDH1 activity, leading to production of D-2-hydroxyglutarate (2-HG), epigenetic dysregulation, and impaired myeloid differentiation. Biochemical profiling demonstrated that ivosidenib potently inhibits multiple IDH1 R132 variants, including R132L, with similar low nanomolar activity (civic.EID:12903). In the phase 3 AGILE trial of patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), ivosidenib plus azacitidine significantly improved overall survival compared with placebo plus azacitidine (median 24.0 vs 7.9 months; HR 0.44), although variant-specific efficacy analyses were not performed and R132L was present in only 3 patients in the ivosidenib arm (civic.EID:12899). Long-term follow-up confirmed sustained survival benefit in the overall IDH1-mutated AML cohort (median OS 29.3 vs 7.9 months; HR 0.42), with no reported association between treatment outcomes and specific IDH1 variant subtype (civic.EID:12901). Together, the available evidence supports ivosidenib-based sensitivity for IDH1 R132-mutated AML broadly, while direct clinical evidence specific to R132L remains limited. Based on FDA approval of ivosidenib for IDH1-mutated AML and supporting 2026 NCCN recommendations, IDH1 R132L confer Tier I \u2013 Level A classification under AMP/ASCO/CAP guidelines.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/234" ], "proposition": "#/proposition/civic.proposition:xBin6oRIMlUOrdfXP-Ry3sYdR-Kx-JS4", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12899", "https://civicdb.org/links/evidence/12901", "https://civicdb.org/links/evidence/12903" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:PfWyld_FxOd5gbJ6eArwENTH7Bq9z8kI", "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:235": { "id": "civic.aid:235", "type": "Statement", "description": "IDH1 R132L is a recurrent missense variant affecting the catalytic arginine residue at codon 132 of IDH1. Functional studies demonstrate that IDH1 R132 mutations exhibit neomorphic activity resulting in production of 2-hydroxyglutarate and that inhibition of mutant IDH1 is associated with reduced 2-hydroxyglutarate levels and induction of myeloid differentiation in IDH1-mutant acute myeloid leukemia (AML) models (OS2; civic.EID:12902). Clinical studies identified IDH1 R132L in patients with newly diagnosed IDH1-mutated AML, supporting its occurrence in human malignancy (civic.EID:12898, civic.EID:12900). The R132L variant occurs at the well-established IDH1 R132 hotspot residue (OS3), is predicted to be a driver mutation (CHASMplus score 0.91-0.933 > VECS gene-specific cutoff of 0.44; OP1), and is absent from population databases (gnomAD v4.1.0; OP4). Together, these criteria indicate that IDH1 R132L is oncogenic, with a score of 10.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/235" ], "proposition": "#/proposition/civic.proposition:M2UMVmScyNyFtBKtytsREiGhea2PqbOH", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "definitive" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12898", "https://civicdb.org/links/evidence/12900", "https://civicdb.org/links/evidence/12902" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "in_silico_impact_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:251": { "id": "civic.aid:251", "type": "Statement", "description": "MAP2K1 P124S causes increased colony formation and increased pERK/ERK ratio (civic.eid:12986, OS2). In cancerhotspots.org there are more than 10 (15) samples with the same amino acid change and less than 50 (25) samples with a somatic variant at the same amino acid position (OM3). The variant is absent in gnomAD database (v4.1.0) (OP4). Together these criteria indicate that P124S is likely oncogenic, with a score of 7. Variant classification was done using ClinGen Somatic MAPK/ERK pathway SC-VCEP guidelines.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/251" ], "proposition": "#/proposition/civic.proposition:5ApL2QQsXFCk0CnKObMuYDSs3vGv9eCE", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12986" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "moderate" } }, "scoreOfEvidenceProvided": 2, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OM3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:252": { "id": "civic.aid:252", "type": "Statement", "description": "The variant p.Ser214Phe (NM_001654.5:c.641C>T ; CA16602805 ) in the ARAF gene was classified as Likely Oncogenic in malignant neoplasms by the ClinGen MAPK/ERK Pathway SC-VCEP, using SC-VCEP Specifications created in 2026. This variant satisfies the following criteria: OS2, functional evidence PMID:\u00a024569458, increased colony formation, increased pMEK/MEK ratio; \nOP3, p.S214F change count in cancerhotspots.org is < 10 (4) \nOP4, absent in controls, no entry in gnomAD. This results in 1 Strong, AND 2 supporting evidence codes and a total of 6 points. Additional notes on this curation record are as follows: None.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/252" ], "proposition": "#/proposition/civic.proposition:gLM8P3kTCL6843M_KCOWQdqkMQciAVpi", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12972" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:253": { "id": "civic.aid:253", "type": "Statement", "description": "The variant p.Ser257Leu (NM_002880.4:c.770C>T ; CA235334 ) in the RAF1 (CRAF) gene was classified as Likely Oncogenic in malignant neoplasms by the ClinGen MAPK/ERK Pathway SC-VCEP, using SC-VCEP Specifications created in 2026. This variant satisfies the following criteria: OS2, functional evidence PMID:\u00a024569458, increased colony formation, increased pMEK/MEK ratio; PMID:\u00a038127827, increased pERK/ERK ratio; OM1, variant in exon 7 (AA 227-278); OP4, absent in controls, no entry in gnomAD. This results in 1 Strong, 1 moderate AND 1 supporting evidence codes and a total of 7 points. Additional notes on this curation record are as follows: The count in cancerhotspots.org is 24 (25 samples with a somatic variant at the same amino acid position); relevant tumor type(s): neoplasms.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/253" ], "proposition": "#/proposition/civic.proposition:-OjgCu1W5BBfsmILfRzuYMzH6A2XcBKc", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12991" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_domain_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "moderate" } }, "scoreOfEvidenceProvided": 2, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OM1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:277": { "id": "civic.aid:277", "type": "Statement", "description": "The ERBB2 G292R variant is a rare variant that has been observed in cancers of the hepatobiliary and urinary tracts; it is not prevalent in breast cancer. This variant is located in the extracellular cysteine-rich domain C1 that is critical for dimerization (civic.EID:12118) (OM1). Functional data from in vitro assays of cell growth and focus formation are limited, and results have been mixed (civic.EID:12116, civic.EID:12117, civic.EID:12118)(OS2_Moderate). CHASMplus scores do not indicate that this is a deleterious mutation (scores between 0.377-0.567 do not reach the VECS gene-specific cutoff of 0.68 for ERBB2). No instances are reported in cancerhotspots (V2). The variant is absent in the gnomAD database (v4.1.0, OP4). In the absence of stronger functional data, these criteria indicate that G292R remains a Variant of Unknown Significance (VUS), with a score of 5.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/277" ], "proposition": "#/proposition/civic.proposition:D7nwuyFg7eo_QmyPHgO7vud7WnrN60gf", "direction": "supports", "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "uncertain significance" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12116", "https://civicdb.org/links/evidence/12117", "https://civicdb.org/links/evidence/12118" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_domain_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "moderate" } }, "scoreOfEvidenceProvided": 2, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OM1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "moderate" } }, "scoreOfEvidenceProvided": 2, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2_moderate" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:278": { "id": "civic.aid:278", "type": "Statement", "description": "The ERBB2 V777L variant is found in breast cancer and at low frequency in other solid tumors; it may or may not be associated with gene amplification (civic.EID:12103). It displays greater tyrosine kinase activity than wild-type in multiple in vitro kinase assays (civic.EID:12103). It induces anchorage-independent growth and tumor formation in xenografts when stably over-expressed in cultured murine NCI-H508 colon cancer cells (civic.EID:4452) NIH-3T3 cells and MCF10A human breast epithelial cells (civic.EID:12103, civic.EID:12104 (OS2). This variant is located in the ATP-binding site of the tyrosine kinase catalytic domain (OM1). ERBB2 V777L is predicted to be deleterious (CHASMplus scores between 0.761-0.803 exceed the VECS gene-specific cutoff of 0.68 for ERBB2, OP1). Seventeen instances of the variant occur in cancerhotspots.org (V2), 6 in breast, 4 in colon, and 7 in other cancer types (OP3). The variant is absent in the gnomAD database (v4.1.0, OP4). Together these criteria indicate that V777L is likely oncogenic, with a score of 9.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/278" ], "proposition": "#/proposition/civic.proposition:eOVYQU3IrlXIyUgUj2lJhemmLJCXaWaR", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "likely oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/12103", "https://civicdb.org/links/evidence/4452", "https://civicdb.org/links/evidence/12104" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_domain_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "moderate" } }, "scoreOfEvidenceProvided": 2, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OM1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "in_silico_impact_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:310": { "id": "civic.aid:310", "type": "Statement", "description": "The H3C2 K28M (K27M) mutation has the same amino acid change as an established oncogenic variant at the canonical hotspot for histone mutant glioma (OS1, 4 points). H3C2 K27M variant causes a global reduction in H3K27me3 compared to non-K27M tumors (civic EID: 131177). Functional studies demonstrated that the homologous H3.1 K27M variant causes a global reduction in H3K27me3 through dominant negative mechanism of inhibition of PRC2, establishing a biologically relevant oncogenic mechanism applicable to H3C2 K27M (civic.EID:13177) (OS2, 4 points). The affected lysine 27 residue represents a recurrent somatic hotspot in more than 20 reported tumors harboring pathogenic variants at this amino acid position (OS3). It has been documented in the diffuse midline glioma (OP2). This variant is not known as a recurrent germline variant and is not reported as a population polymorphism. (OP4). The listed evidence indicates the H3 variant to be oncogenic utilizing the ClinGen Histone H3 Somatic Cancer Variant Curation Expert Panel criteria (OS1+OS2+OS3+OP2+OP4).", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/310" ], "proposition": "#/proposition/civic.proposition:883y2qcE4Rln9dTylWntFVeRoW46T9pL", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "definitive" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/13177", "https://civicdb.org/links/evidence/13178" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "amino_acid_analogy_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "single_genetic_etiology_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP2" } } } ] }, "civic.aid:33": { "id": "civic.aid:33", "type": "Statement", "description": "Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are the most common mutations in acute myeloid leukemia (AML). 5 to 10% of AML is associated with activating point mutations in the FLT3 tyrosine kinase domain (TKD), particularly at the D835 residue. FLT3 D835 mutations are a common mechanism of clinical resistance to type II FLT3 inhibitors (sorafenib, quizartinib and ponatinib), which bind only the inactive kinase conformation. However, gilteritinib, a type I oral inhibitor of FLT3 and AXL, demonstrated preclinical activity against type II FLT3 inhibitor resistance-conferring D835 mutations and clinical activity as monotherapy in Relapsed/Refractory (R/R) FLT3-mutated AML in multiple clinical trials. The 2017 FDA approved FLT3 mutation companion diagnostic assay can detect a D835 or I836 mutation, but cannot distinguish which of these residues is mutated. In 2018, the US Food and Drug Administration (FDA) approved gilteritinib as the first FLT3 inhibitor indicated for use as monotherapy for R/R AML with FLT3 D835.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/33" ], "proposition": "#/proposition/civic.proposition:54GnST475stfhfOLYqYSHOZBajtKPWfB", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/7728", "https://civicdb.org/links/evidence/7283", "https://civicdb.org/links/evidence/8106", "https://civicdb.org/links/evidence/8108", "https://civicdb.org/links/evidence/8351" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:zV75hr3o6OVknaKJG4D8hsqdycyKaDpQ", "hasEvidenceItems": [ "#/evidence/civic.eid:7283", "#/evidence/civic.eid:8106", "#/evidence/civic.eid:8108", "#/evidence/civic.eid:8351" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:38": { "id": "civic.aid:38", "type": "Statement", "description": "The constitutively activating FLT3 internal tandem duplication (ITD) mutation appears in approximately 20-30% of AML patients and are associated with high risk, high relapse rates and poor clinical outcome. The type I selective second-generation oral inhibitor, gilteritinib, received initial global approval for use to treat adults with relapsed or refractory (R/R) FLT3 ITD positive AML in Japan in September 2018. Based on interim results of the ADMIRAL trail (Perl AE, et al., 2019), the FDA approved the drug for treatment of adult R/R AML with FLT3 ITD mutations in November 2018. The FDA approved companion diagnostic, LeukoStrat CDx FLT3 Mutation assay.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/38" ], "proposition": "#/proposition/civic.proposition:LjKTC4cvdsCNl52GXtVG_mtZHgd2X1JL", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/7728", "https://civicdb.org/links/evidence/7283", "https://civicdb.org/links/evidence/8924", "https://civicdb.org/links/evidence/8923" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:13pQSub9TfI2E2_x3lQaV9W4vsofZMLN", "hasEvidenceItems": [ "#/evidence/civic.eid:7283", "#/evidence/civic.eid:8924", "#/evidence/civic.eid:8923" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:5": { "id": "civic.aid:5", "type": "Statement", "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor erlotinib is associated with improved progression free survival over chemotherapy in EGFR L858R patients (civic.EID:885).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/5" ], "proposition": "#/proposition/civic.proposition:s1e8HpFqnVZBo4v3NGTHJG5WJ-5QSZ31", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/2994", "https://civicdb.org/links/evidence/229", "https://civicdb.org/links/evidence/885", "https://civicdb.org/links/evidence/4290", "https://civicdb.org/links/evidence/3811", "https://civicdb.org/links/evidence/4265", "https://civicdb.org/links/evidence/4285", "https://civicdb.org/links/evidence/4291" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:mCQYLirVeuIXrHZ2ElPCxdxLKC24cz_-", "hasEvidenceItems": [ "#/evidence/civic.eid:2994", "#/evidence/civic.eid:229", "#/evidence/civic.eid:885", "#/evidence/civic.eid:4290", "#/evidence/civic.eid:3811", "#/evidence/civic.eid:4265", "#/evidence/civic.eid:4285", "#/evidence/civic.eid:4291" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:55": { "id": "civic.aid:55", "type": "Statement", "description": "In vitro studies indicate that the S249C variant affects normal FGFR3 function in a manner consistent with oncogenic activation. The S249C variant results in constitutive FGFR3 activation, ligand-independent signaling, cellular transformation, tumor formation in vivo, and oncogene dependence in bladder cancer models (civic.EID:8855, civic.EID:10386, civic.EID:8811) (OS2). FGFR3 codon 249 is identified as a statistically enriched hotspot in the Cancer Hotspots database. The Cancer Hotspots dataset contains 50 or more samples with a somatic variant at this codon, with the S249C variant present in 10 or more samples (OS3). The S249C variant has a score of 0.902 from the REVEL in silico prediction tool (OP1). The FGFR3 c.746C>G (p.S249C) variant is absent in the gnomAD database (OP4). These codes lead to an Oncogenicity score of 10 (OS2 [4]; OS3 [4]; OP1 [1]; OP4 [1]). Therefore, the FGFR3 S249C variant is classified as Oncogenic according to the FGFR SC-VCEP Oncogenicity specifications.", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "guideline", "reportedIn": "#/source/pmid:35101336" }, "reportedIn": [ "https://civicdb.org/links/assertion/55" ], "proposition": "#/proposition/civic.proposition:yqxCLfkXteFOYvE-1GtJ9wXWc1HCBEg0", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "definitive" } }, "classification": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "oncogenic" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/7306", "https://civicdb.org/links/evidence/4871", "https://civicdb.org/links/evidence/8853", "https://civicdb.org/links/evidence/10386", "https://civicdb.org/links/evidence/7941", "https://civicdb.org/links/evidence/8642", "https://civicdb.org/links/evidence/8811", "https://civicdb.org/links/evidence/8854", "https://civicdb.org/links/evidence/8855" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "functional_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS2" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "somatic_hotspot_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "strong" } }, "scoreOfEvidenceProvided": 4, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OS3" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "in_silico_impact_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP1" } } }, { "type": "EvidenceLine", "specifiedBy": { "type": "Method", "name": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "methodType": "population_data_assessment", "reportedIn": "#/source/pmid:35101336" }, "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "supporting" } }, "scoreOfEvidenceProvided": 1, "evidenceOutcome": { "type": "MappableConcept", "primaryCoding": { "system": "ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022", "code": "OP4" } } } ] }, "civic.aid:6": { "id": "civic.aid:6", "type": "Statement", "description": "L858R is among the most common sensitizing EGFR mutations in NSCLC, and is assessed via DNA mutational analysis, including Sanger sequencing and next generation sequencing methods. Tyrosine kinase inhibitor afatinib is FDA approved as a first line systemic therapy in NSCLC with sensitizing EGFR mutation (civic.EID:2997).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/6" ], "proposition": "#/proposition/civic.proposition:s1e8HpFqnVZBo4v3NGTHJG5WJ-5QSZ31", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/2997", "https://civicdb.org/links/evidence/879", "https://civicdb.org/links/evidence/982", "https://civicdb.org/links/evidence/883", "https://civicdb.org/links/evidence/968", "https://civicdb.org/links/evidence/2629" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:3n7vu1vTbv9cSmlyrCq4fNuh_5YNzo1c", "hasEvidenceItems": [ "#/evidence/civic.eid:2997", "#/evidence/civic.eid:879", "#/evidence/civic.eid:982", "#/evidence/civic.eid:883", "#/evidence/civic.eid:968", "#/evidence/civic.eid:2629" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:7": { "id": "civic.aid:7", "type": "Statement", "description": "Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy than with BRAF inhibitor alone.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/7" ], "proposition": "#/proposition/civic.proposition:yIxQ2zvDhwzUh5UGOy90mmnnkbxU3a3z", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/6178", "https://civicdb.org/links/evidence/6938", "https://civicdb.org/links/evidence/3758", "https://civicdb.org/links/evidence/6940" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:I_7vf1IZYIb8nUrIGtn0YyJ6EGctsiuq", "hasEvidenceItems": [ "#/evidence/civic.eid:6178", "#/evidence/civic.eid:6938", "#/evidence/civic.eid:3758", "#/evidence/civic.eid:6940" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:80": { "id": "civic.aid:80", "type": "Statement", "description": "Clear cell sarcoma of the kidney is a rare renal cancer in children with the majority harboring an internal tandem duplication in BCOR (BCOR ITD) associated with BCOR overexpression. Professional guidelines (WHO) list BCOR ITD, BCOR::CCNB3, or YWHAE::NUTM2 as desirable diagnostic criteria for clear cell sarcoma of the kidney (WHO classification of tumours series, 5th ed.; vol. 7).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/80" ], "proposition": "#/proposition/civic.proposition:gCzgcgmlESiieuasYb8ZzTc6Vta2FVBC", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/10801", "https://civicdb.org/links/evidence/10802", "https://civicdb.org/links/evidence/11423", "https://civicdb.org/links/evidence/11424" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:tRhMvcZfPGf0hkRHp154Da-8eujCQtd9", "hasEvidenceItems": [ "#/evidence/civic.eid:10801", "#/evidence/civic.eid:11423", "#/evidence/civic.eid:11424" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:85": { "id": "civic.aid:85", "type": "Statement", "description": "KIT D816V is located within the activation loop of the KIT kinase domain and is a recurrent somatic hotspot mutation in systemic mastocytosis (civic.EID:12913, civic.EID:12917). D816V constitutively activates KIT, promoting ligand-independent signaling and uncontrolled mast cell proliferation (civic.EID:12411). D816V disrupts interactions within the activation loop and weakens JMR\u2013kinase domain interactions, destabilizing the inactive KIT conformation and reducing effective imatinib binding (civic.EID:12915). Consistent with this mechanism, systemic mastocytosis patients harboring KIT D816V exhibit resistance to imatinib, with diminished clinical responses compared with patients harboring wild-type KIT (civic.EID:8360, civic.EID:11160, civic.EID:11369). Thus, imatinib is not expected to provide clinical benefit in systemic mastocytosis patients harboring KIT D816V, and alternative therapeutic approaches are recommended. The KIT D816V Assay (ARUP Laboratories, Inc.) received an FDA-companion diagnostic approval on December 18, 2015.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/85" ], "proposition": "#/proposition/civic.proposition:OfVCu8-bsOZuVUHXfIS0F_qe_4E1ljBy", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11160", "https://civicdb.org/links/evidence/8360", "https://civicdb.org/links/evidence/12411", "https://civicdb.org/links/evidence/11369", "https://civicdb.org/links/evidence/12913", "https://civicdb.org/links/evidence/12915", "https://civicdb.org/links/evidence/12917", "https://civicdb.org/links/evidence/2451", "https://civicdb.org/links/evidence/7465" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:Q2LyLAq0lcgnuq6VfFUHF6mwdyPKvb8V", "hasEvidenceItems": [ "#/evidence/civic.eid:11160", "#/evidence/civic.eid:8360", "#/evidence/civic.eid:2451", "#/evidence/civic.eid:7465" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:9": { "id": "civic.aid:9", "type": "Statement", "description": "ACVR1 G328V mutations occur within the kinase domain, leading to activation of downstream signaling. Exclusively seen in high-grade pediatric gliomas, supporting diagnosis of diffuse intrinsic pontine glioma.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/9" ], "proposition": "#/proposition/civic.proposition:fOBF0e3ZunhJ23AdC3O3m2Vg5k_ARxkv", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "potential" } }, "classification": { "type": "MappableConcept", "name": "Tier II", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier ii" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/4846", "https://civicdb.org/links/evidence/6955" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:H6qvcvpF_jzQmVg72PCxDbwJIAsMh58Q", "hasEvidenceItems": [ "#/evidence/civic.eid:4846", "#/evidence/civic.eid:6955" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "C" } } } ] }, "civic.aid:91": { "id": "civic.aid:91", "type": "Statement", "description": "PAX5 missense variant p.Pro80Arg defines a genetic subtype of B-lymphoblastic leukemia characterized by a distinctive expression profile and recognized in the WHO and ICC classification. PAX5 P80R B-ALL accounts for approximately 2% of childhood B-ALLs. All cases feature the universal P80R (p.Pro80Arg) mutation and a deletion or mutation of the remaining PAX5 allele. Mutations in RAS and JAK signaling genes are common as secondary changes.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/91" ], "proposition": "#/proposition/civic.proposition:daVYR2l_r9g3-HYGQ0pp7kvSMsx2WazE", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11519", "https://civicdb.org/links/evidence/7290", "https://civicdb.org/links/evidence/7291" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:V1DAV6g-gapeiIUSbiZoxU8IGR0WsPK5", "hasEvidenceItems": [ "#/evidence/civic.eid:11519", "#/evidence/civic.eid:7290", "#/evidence/civic.eid:7291" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:93": { "id": "civic.aid:93", "type": "Statement", "description": "CNS neuroblastoma, FOXR2-activated, is a rare pediatric embryonal tumor characterized by activation of the FOXR2 gene. This activation typically results from structural rearrangements involving upstream regions of FOXR2, including inter- and intra-chromosomal rearrangements with other genomic loci. These alterations retain the full FOXR2 coding sequence and lead to elevated FOXR2 expression, likely driven by enhancer hijacking or promoter switching. According to the 5th edition of the WHO Classification of Tumors of the Central Nervous System, FOXR2 activation through gene fusions or structural rearrangements is a molecular feature of CNS neuroblastoma, FOXR2-activated. While high FOXR2 expression is a feature of this entity, it may be observed in a subset of other tumors, including certain high grade gliomas and, rarely, medulloblastomas. Importantly, FOXR2-activated CNS neuroblastoma forms a distinct DNA methylation cluster, making methylation profiling a valuable tool for its accurate diagnosis.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/93" ], "proposition": "#/proposition/civic.proposition:2DF5V_36ADtwjKMpkJ8XGqVUejySrKXL", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/11527", "https://civicdb.org/links/evidence/11528", "https://civicdb.org/links/evidence/12521" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:aW1DTrk0v0DOnN9-YfoKlGSuQu4Z3fi9", "hasEvidenceItems": [ "#/evidence/civic.eid:11527", "#/evidence/civic.eid:11528", "#/evidence/civic.eid:12521" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] }, "civic.aid:95": { "id": "civic.aid:95", "type": "Statement", "description": "CNS tumor with BCOR ITD are characterized by BCOR exon 15 ITD (internal tandem duplication). Professional guidelines (WHO) list an ITD in exon 15 of BCOR as an essential diagnostic criterion with a DNA methylation profile aligned with CNS tumor with BCOR ITD as essential for unresolved cases. BCOR ITDs are present in 3% of CNS high grade neuroepithelial tumors, with variable morphological features including a oval to spindle shaped cells, in solid growth patterns or with perivascular pseudorosettes. Gene expression of BCOR has been shown to be increased in CNS tumor with BCOR ITD. BCOR immunohistochemistry is a sensitive marker for CNS tumor with BCOR ITD.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/95" ], "proposition": "#/proposition/civic.proposition:hhoVDxhNegotNWdwa6eHK3eUYaW9KIJK", "direction": "supports", "strength": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "strong" } }, "classification": { "type": "MappableConcept", "name": "Tier I", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier i" } }, "hasEvidence": [ "https://civicdb.org/links/evidence/10800", "https://civicdb.org/links/evidence/10804", "https://civicdb.org/links/evidence/10887", "https://civicdb.org/links/evidence/11581" ], "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:OGVPQeSJXDNHxxLQB6ST4m00P969TG9g", "hasEvidenceItems": [ "#/evidence/civic.eid:10800", "#/evidence/civic.eid:10887", "#/evidence/civic.eid:11581" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "type": "MappableConcept", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "A" } } } ] } }, "metadata": { "implementationVersions": { "VRSPython": "2.4.0a6", "CatVRSPython": "0.8.0a6", "VASpecPython": "0.5.0a6" }, "specificationVersions": { "GKMCore": "1.3.0", "VRS": "2.1.1", "CatVRS": "1.1.1", "VASpec": "1.1.0" }, "createdAt": "2026-10-02", "bundleFormat": "civic-gkm-bundle", "bundleFormatVersion": "0.1.0-a0", "statistics": { "collections": { "sequenceReference": { "count": 41 }, "location": { "count": 56, "types": { "SequenceLocation": 56 } }, "variant": { "count": 80, "types": { "Allele": 56, "Coding": 22, "CopyNumberChange": 2 } }, "feature": { "count": 31 }, "molecularProfile": { "count": 44 }, "disease": { "count": 32 }, "phenotype": { "count": 13 }, "conditionSet": { "count": 54 }, "therapy": { "count": 20 }, "therapyGroup": { "count": 9 }, "variantOrigin": { "count": 3 }, "source": { "count": 102 }, "method": { "count": 1 }, "organization": { "count": 1 }, "proposition": { "count": 130, "types": { "VariantClinicalSignificanceProposition": 30, "VariantDiagnosticProposition": 48, "VariantOncogenicityProposition": 10, "VariantPrognosticProposition": 4, "VariantTherapeuticResponseProposition": 38 } }, "evidence": { "count": 116 }, "assertion": { "count": 44 } } } }, "failedAssertionIds": [ 3, 4, 8, 14, 17, 18, 21, 24, 34, 39, 41, 43, 51, 52, 56, 57, 58, 59, 60, 61, 62, 63, 71, 74, 76, 79, 86, 87, 92, 97, 98, 99, 100, 101, 102, 103, 106, 107, 108, 109, 110, 111, 116, 118, 119, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 135, 136, 137, 138, 139, 141, 144, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, 163, 164, 166, 169, 170, 171, 179, 181, 182, 186, 187, 188, 189, 190, 191, 192, 194, 197, 205, 207, 208, 212, 213, 214, 217, 219, 223, 227, 228, 243 ] }