From ab2a15c96682a52b90597556d61fef431dc95484 Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 8 May 2026 10:26:27 -0400 Subject: [PATCH 1/9] test: update civic onco assertion test fixture * Add description * Add alleleOriginQualifier + geneContextQualifier to propositions * Update proposition variant: Fix variant aliases, add addtl mapping, add extensions * Add specifiedBy + extensions to Evidence Line --- .../civic-assertion-oncogenicity.yaml | 722 +++++++++++++++++- 1 file changed, 706 insertions(+), 16 deletions(-) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 4ce0a6c6..a940b832 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -1,5 +1,24 @@ 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." proposition: type: VariantOncogenicityProposition objectTumorType: @@ -12,6 +31,49 @@ proposition: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor + alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic + geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant @@ -24,7 +86,7 @@ proposition: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -43,6 +105,47 @@ proposition: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C strength: primaryCoding: code: likely @@ -66,10 +169,32 @@ specifiedBy: type: Document methodType: guideline type: Method +contributions: + - activityType: approval.last_reviewed + contributor: + description: + The CIViC Organization (formerly “The McDonnell Genome Institute” + CIViC organization) comprises the founders, developers, editors, + curators, and administrators who build and maintain the knowledgebase, + based at Washington University in St. Louis. This group is dedicated to + ensuring that high-quality cancer variant interpretations are broadly + accessible for precision oncology. One of their main roles is evaluating + and synthesizing crowdsourced community contributions into formal + clinical Assertions. Once these Assertions meet the strict criteria of + the CIViC standard operating procedure, core approval members approve + them for 1-star submission to the ClinVar CIViC organization. + extensions: + - name: is_approved_vcep + value: false + id: civic.organization:1 + name: CIViC + type: Agent + date: 2026-04-16:00:00:00 + type: Contribution hasEvidenceLines: - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition + targetProposition: # identical to VariantOncogenicityStatement.proposition type: VariantOncogenicityProposition objectTumorType: id: civic.did:15 @@ -81,10 +206,54 @@ hasEvidenceLines: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor + alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic + geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant - description: RET M918T is the most common somatically acquired mutation in + description: + RET M918T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation @@ -93,7 +262,7 @@ hasEvidenceLines: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -112,6 +281,47 @@ hasEvidenceLines: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: moderate @@ -121,9 +331,37 @@ hasEvidenceLines: code: OM1 system: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 scoreOfEvidenceProvided: 2 + specifiedBy: + type: Method + methodType: OM1 + name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 + reportedIn: + doi: 10.1016/j.gim.2022.01.001 + id: pmid:35101336 + name: Horak et al., 2022, Genet Med. + pmid: "35101336" + title: + "Standards for the classification of pathogenicity of somatic variants in + cancer (oncogenicity): Joint recommendations of Clinical Genome + Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant + Interpretation for Cancer Consortium (VICC)" + type: Document + urls: + - https://doi.org/10.1016/j.gim.2022.01.001 + - https://pubmed.ncbi.nlm.nih.gov/35101336/ + extensions: # These are the same across all evidence lines + - name: citations + value: + - 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 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition + targetProposition: # identical to VariantOncogenicityStatement.proposition type: VariantOncogenicityProposition objectTumorType: id: civic.did:15 @@ -135,10 +373,54 @@ hasEvidenceLines: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor + alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic + geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant - description: RET M918T is the most common somatically acquired mutation in + description: + RET M918T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation @@ -147,7 +429,7 @@ hasEvidenceLines: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -166,6 +448,47 @@ hasEvidenceLines: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: strong @@ -175,9 +498,37 @@ hasEvidenceLines: code: OS2 system: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 scoreOfEvidenceProvided: 4 + specifiedBy: + type: Method + methodType: OS2 + name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 + reportedIn: + doi: 10.1016/j.gim.2022.01.001 + id: pmid:35101336 + name: Horak et al., 2022, Genet Med. + pmid: "35101336" + title: + "Standards for the classification of pathogenicity of somatic variants in + cancer (oncogenicity): Joint recommendations of Clinical Genome + Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant + Interpretation for Cancer Consortium (VICC)" + type: Document + urls: + - https://doi.org/10.1016/j.gim.2022.01.001 + - https://pubmed.ncbi.nlm.nih.gov/35101336/ + extensions: # These are the same across all evidence lines + - name: citations + value: + - 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 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition + targetProposition: # identical to VariantOncogenicityStatement.proposition type: VariantOncogenicityProposition objectTumorType: id: civic.did:15 @@ -189,10 +540,54 @@ hasEvidenceLines: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor + alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic + geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant - description: RET M918T is the most common somatically acquired mutation in + description: + RET M918T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation @@ -201,7 +596,7 @@ hasEvidenceLines: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -220,6 +615,47 @@ hasEvidenceLines: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: supporting @@ -229,9 +665,37 @@ hasEvidenceLines: code: OP4 system: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 scoreOfEvidenceProvided: 1 + specifiedBy: + type: Method + methodType: OP4 + name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 + reportedIn: + doi: 10.1016/j.gim.2022.01.001 + id: pmid:35101336 + name: Horak et al., 2022, Genet Med. + pmid: "35101336" + title: + "Standards for the classification of pathogenicity of somatic variants in + cancer (oncogenicity): Joint recommendations of Clinical Genome + Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant + Interpretation for Cancer Consortium (VICC)" + type: Document + urls: + - https://doi.org/10.1016/j.gim.2022.01.001 + - https://pubmed.ncbi.nlm.nih.gov/35101336/ + extensions: # These are the same across all evidence lines + - name: citations + value: + - 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 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition + targetProposition: # identical to VariantOncogenicityStatement.proposition type: VariantOncogenicityProposition objectTumorType: id: civic.did:15 @@ -243,10 +707,54 @@ hasEvidenceLines: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor + alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic + geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant - description: RET M918T is the most common somatically acquired mutation in + description: + RET M918T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation @@ -255,7 +763,7 @@ hasEvidenceLines: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -274,6 +782,47 @@ hasEvidenceLines: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: supporting @@ -283,9 +832,37 @@ hasEvidenceLines: code: OP1 system: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 scoreOfEvidenceProvided: 1 + specifiedBy: + type: Method + methodType: OP1 + name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 + reportedIn: + doi: 10.1016/j.gim.2022.01.001 + id: pmid:35101336 + name: Horak et al., 2022, Genet Med. + pmid: "35101336" + title: + "Standards for the classification of pathogenicity of somatic variants in + cancer (oncogenicity): Joint recommendations of Clinical Genome + Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant + Interpretation for Cancer Consortium (VICC)" + type: Document + urls: + - https://doi.org/10.1016/j.gim.2022.01.001 + - https://pubmed.ncbi.nlm.nih.gov/35101336/ + extensions: # These are the same across all evidence lines + - name: citations + value: + - 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 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition + targetProposition: # identical to VariantOncogenicityStatement.proposition type: VariantOncogenicityProposition objectTumorType: id: civic.did:15 @@ -297,10 +874,54 @@ hasEvidenceLines: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor + alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic + geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant - description: RET M918T is the most common somatically acquired mutation in + description: + RET M918T is the most common somatically acquired mutation in medullary thyroid cancer (MTC). While there currently are no RET-specific inhibiting agents, promiscuous kinase inhibitors have seen some success in treating RET overactivity. Data suggests however, that the M918T mutation @@ -309,7 +930,7 @@ hasEvidenceLines: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -328,6 +949,47 @@ hasEvidenceLines: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: supporting @@ -337,3 +999,31 @@ hasEvidenceLines: code: OP3 system: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 scoreOfEvidenceProvided: 1 + specifiedBy: + type: Method + methodType: OP3 + name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 + reportedIn: + doi: 10.1016/j.gim.2022.01.001 + id: pmid:35101336 + name: Horak et al., 2022, Genet Med. + pmid: "35101336" + title: + "Standards for the classification of pathogenicity of somatic variants in + cancer (oncogenicity): Joint recommendations of Clinical Genome + Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant + Interpretation for Cancer Consortium (VICC)" + type: Document + urls: + - https://doi.org/10.1016/j.gim.2022.01.001 + - https://pubmed.ncbi.nlm.nih.gov/35101336/ + extensions: # These are the same across all evidence lines + - name: citations + value: + - 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 From 8cd4b63630a959902ff3aec49a3f839a0ebec641 Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 29 May 2026 11:30:51 -0400 Subject: [PATCH 2/9] update method types --- tests/fixtures/civic-assertion-oncogenicity.yaml | 10 +++++----- 1 file changed, 5 insertions(+), 5 deletions(-) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index a940b832..69903227 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -333,7 +333,7 @@ hasEvidenceLines: scoreOfEvidenceProvided: 2 specifiedBy: type: Method - methodType: OM1 + methodType: functional_domain_location name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 reportedIn: doi: 10.1016/j.gim.2022.01.001 @@ -500,7 +500,7 @@ hasEvidenceLines: scoreOfEvidenceProvided: 4 specifiedBy: type: Method - methodType: OS2 + methodType: functional_assay name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 reportedIn: doi: 10.1016/j.gim.2022.01.001 @@ -667,7 +667,7 @@ hasEvidenceLines: scoreOfEvidenceProvided: 1 specifiedBy: type: Method - methodType: OP4 + methodType: population_frequency name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 reportedIn: doi: 10.1016/j.gim.2022.01.001 @@ -834,7 +834,7 @@ hasEvidenceLines: scoreOfEvidenceProvided: 1 specifiedBy: type: Method - methodType: OP1 + methodType: computational_prediction name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 reportedIn: doi: 10.1016/j.gim.2022.01.001 @@ -1001,7 +1001,7 @@ hasEvidenceLines: scoreOfEvidenceProvided: 1 specifiedBy: type: Method - methodType: OP3 + methodType: somatic_hotspot_recurrence name: ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022 reportedIn: doi: 10.1016/j.gim.2022.01.001 From 43c83fc7d930a12f0ca7acce5d26e580a1519e1f Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 29 May 2026 11:32:14 -0400 Subject: [PATCH 3/9] delete redundant target prop --- .../civic-assertion-oncogenicity.yaml | 640 ------------------ 1 file changed, 640 deletions(-) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 69903227..2669ea6a 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -194,134 +194,6 @@ contributions: hasEvidenceLines: - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition - type: VariantOncogenicityProposition - objectTumorType: - id: civic.did:15 - conceptType: Disease - name: Medullary Thyroid Carcinoma - mappings: - - coding: - code: DOID:3973 - system: https://disease-ontology.org/?id= - relation: exactMatch - predicate: isOncogenicFor - alleleOriginQualifier: - extensions: - - name: civic_variant_origin - value: SOMATIC - name: somatic - geneContextQualifier: - conceptType: Gene - 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. - id: civic.gid:42 - mappings: - - coding: - code: "5979" - id: ncbigene:5979 - system: https://www.ncbi.nlm.nih.gov/gene/ - relation: exactMatch - name: RET - subjectVariant: - id: civic.mpid:113 - type: CategoricalVariant - description: - RET M918T is the most common somatically acquired mutation in - medullary thyroid cancer (MTC). While there currently are no RET-specific - inhibiting agents, promiscuous kinase inhibitors have seen some success in - treating RET overactivity. Data suggests however, that the M918T mutation - may lead to drug resistance, especially against the VEGFR-inhibitor - motesanib. It has also been suggested that RET M918T leads to more - aggressive MTC with a poorer prognosis. - name: RET M918T - aliases: - - MET918THR - mappings: - - coding: - code: rs74799832 - system: https://www.ncbi.nlm.nih.gov/snp/ - relation: relatedMatch - - coding: - code: CA009082 - system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= - relation: relatedMatch - - coding: - code: "13919" - system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ - relation: relatedMatch - - coding: - id: civic.mpid:113 - code: "113" - system: https://civicdb.org/links/molecular_profile/ - relation: exactMatch - - coding: - code: "113" - extensions: - - name: subtype - value: gene_variant - - name: variant_types - value: - - coding: - code: SO:0001583 - id: civic.variant_type:47 - name: Missense Variant - system: http://www.sequenceontology.org/browser/current_svn/term/ - relation: exactMatch - id: civic.vid:113 - name: M918T - system: https://civicdb.org/links/variant/ - relation: exactMatch - extensions: - - name: CIViC Molecular Profile Score - value: 139.0 - - name: expressions - value: - - syntax: hgvs.c - value: NM_020975.4:c.2753T>C - - syntax: hgvs.p - value: NP_065681.1:p.Met918Thr - - syntax: hgvs.c - value: ENST00000355710.3:c.2753T>C - - syntax: hgvs.g - value: NC_000010.10:g.43617416T>C - - name: CIViC representative coordinate - value: - chromosome: "10" - ensembl_version: 75 - reference_bases: T - reference_build: GRCh37 - representative_transcript: ENST00000355710.3 - start: 43617416 - stop: 43617416 - type: coordinates - variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: moderate @@ -361,134 +233,6 @@ hasEvidenceLines: - https://civicdb.org/links/evidence/12709 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition - type: VariantOncogenicityProposition - objectTumorType: - id: civic.did:15 - conceptType: Disease - name: Medullary Thyroid Carcinoma - mappings: - - coding: - code: DOID:3973 - system: https://disease-ontology.org/?id= - relation: exactMatch - predicate: isOncogenicFor - alleleOriginQualifier: - extensions: - - name: civic_variant_origin - value: SOMATIC - name: somatic - geneContextQualifier: - conceptType: Gene - 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. - id: civic.gid:42 - mappings: - - coding: - code: "5979" - id: ncbigene:5979 - system: https://www.ncbi.nlm.nih.gov/gene/ - relation: exactMatch - name: RET - subjectVariant: - id: civic.mpid:113 - type: CategoricalVariant - description: - RET M918T is the most common somatically acquired mutation in - medullary thyroid cancer (MTC). While there currently are no RET-specific - inhibiting agents, promiscuous kinase inhibitors have seen some success in - treating RET overactivity. Data suggests however, that the M918T mutation - may lead to drug resistance, especially against the VEGFR-inhibitor - motesanib. It has also been suggested that RET M918T leads to more - aggressive MTC with a poorer prognosis. - name: RET M918T - aliases: - - MET918THR - mappings: - - coding: - code: rs74799832 - system: https://www.ncbi.nlm.nih.gov/snp/ - relation: relatedMatch - - coding: - code: CA009082 - system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= - relation: relatedMatch - - coding: - code: "13919" - system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ - relation: relatedMatch - - coding: - id: civic.mpid:113 - code: "113" - system: https://civicdb.org/links/molecular_profile/ - relation: exactMatch - - coding: - code: "113" - extensions: - - name: subtype - value: gene_variant - - name: variant_types - value: - - coding: - code: SO:0001583 - id: civic.variant_type:47 - name: Missense Variant - system: http://www.sequenceontology.org/browser/current_svn/term/ - relation: exactMatch - id: civic.vid:113 - name: M918T - system: https://civicdb.org/links/variant/ - relation: exactMatch - extensions: - - name: CIViC Molecular Profile Score - value: 139.0 - - name: expressions - value: - - syntax: hgvs.c - value: NM_020975.4:c.2753T>C - - syntax: hgvs.p - value: NP_065681.1:p.Met918Thr - - syntax: hgvs.c - value: ENST00000355710.3:c.2753T>C - - syntax: hgvs.g - value: NC_000010.10:g.43617416T>C - - name: CIViC representative coordinate - value: - chromosome: "10" - ensembl_version: 75 - reference_bases: T - reference_build: GRCh37 - representative_transcript: ENST00000355710.3 - start: 43617416 - stop: 43617416 - type: coordinates - variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: strong @@ -528,134 +272,6 @@ hasEvidenceLines: - https://civicdb.org/links/evidence/12709 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition - type: VariantOncogenicityProposition - objectTumorType: - id: civic.did:15 - conceptType: Disease - name: Medullary Thyroid Carcinoma - mappings: - - coding: - code: DOID:3973 - system: https://disease-ontology.org/?id= - relation: exactMatch - predicate: isOncogenicFor - alleleOriginQualifier: - extensions: - - name: civic_variant_origin - value: SOMATIC - name: somatic - geneContextQualifier: - conceptType: Gene - 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. - id: civic.gid:42 - mappings: - - coding: - code: "5979" - id: ncbigene:5979 - system: https://www.ncbi.nlm.nih.gov/gene/ - relation: exactMatch - name: RET - subjectVariant: - id: civic.mpid:113 - type: CategoricalVariant - description: - RET M918T is the most common somatically acquired mutation in - medullary thyroid cancer (MTC). While there currently are no RET-specific - inhibiting agents, promiscuous kinase inhibitors have seen some success in - treating RET overactivity. Data suggests however, that the M918T mutation - may lead to drug resistance, especially against the VEGFR-inhibitor - motesanib. It has also been suggested that RET M918T leads to more - aggressive MTC with a poorer prognosis. - name: RET M918T - aliases: - - MET918THR - mappings: - - coding: - code: rs74799832 - system: https://www.ncbi.nlm.nih.gov/snp/ - relation: relatedMatch - - coding: - code: CA009082 - system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= - relation: relatedMatch - - coding: - code: "13919" - system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ - relation: relatedMatch - - coding: - id: civic.mpid:113 - code: "113" - system: https://civicdb.org/links/molecular_profile/ - relation: exactMatch - - coding: - code: "113" - extensions: - - name: subtype - value: gene_variant - - name: variant_types - value: - - coding: - code: SO:0001583 - id: civic.variant_type:47 - name: Missense Variant - system: http://www.sequenceontology.org/browser/current_svn/term/ - relation: exactMatch - id: civic.vid:113 - name: M918T - system: https://civicdb.org/links/variant/ - relation: exactMatch - extensions: - - name: CIViC Molecular Profile Score - value: 139.0 - - name: expressions - value: - - syntax: hgvs.c - value: NM_020975.4:c.2753T>C - - syntax: hgvs.p - value: NP_065681.1:p.Met918Thr - - syntax: hgvs.c - value: ENST00000355710.3:c.2753T>C - - syntax: hgvs.g - value: NC_000010.10:g.43617416T>C - - name: CIViC representative coordinate - value: - chromosome: "10" - ensembl_version: 75 - reference_bases: T - reference_build: GRCh37 - representative_transcript: ENST00000355710.3 - start: 43617416 - stop: 43617416 - type: coordinates - variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: supporting @@ -695,134 +311,6 @@ hasEvidenceLines: - https://civicdb.org/links/evidence/12709 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition - type: VariantOncogenicityProposition - objectTumorType: - id: civic.did:15 - conceptType: Disease - name: Medullary Thyroid Carcinoma - mappings: - - coding: - code: DOID:3973 - system: https://disease-ontology.org/?id= - relation: exactMatch - predicate: isOncogenicFor - alleleOriginQualifier: - extensions: - - name: civic_variant_origin - value: SOMATIC - name: somatic - geneContextQualifier: - conceptType: Gene - 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. - id: civic.gid:42 - mappings: - - coding: - code: "5979" - id: ncbigene:5979 - system: https://www.ncbi.nlm.nih.gov/gene/ - relation: exactMatch - name: RET - subjectVariant: - id: civic.mpid:113 - type: CategoricalVariant - description: - RET M918T is the most common somatically acquired mutation in - medullary thyroid cancer (MTC). While there currently are no RET-specific - inhibiting agents, promiscuous kinase inhibitors have seen some success in - treating RET overactivity. Data suggests however, that the M918T mutation - may lead to drug resistance, especially against the VEGFR-inhibitor - motesanib. It has also been suggested that RET M918T leads to more - aggressive MTC with a poorer prognosis. - name: RET M918T - aliases: - - MET918THR - mappings: - - coding: - code: rs74799832 - system: https://www.ncbi.nlm.nih.gov/snp/ - relation: relatedMatch - - coding: - code: CA009082 - system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= - relation: relatedMatch - - coding: - code: "13919" - system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ - relation: relatedMatch - - coding: - id: civic.mpid:113 - code: "113" - system: https://civicdb.org/links/molecular_profile/ - relation: exactMatch - - coding: - code: "113" - extensions: - - name: subtype - value: gene_variant - - name: variant_types - value: - - coding: - code: SO:0001583 - id: civic.variant_type:47 - name: Missense Variant - system: http://www.sequenceontology.org/browser/current_svn/term/ - relation: exactMatch - id: civic.vid:113 - name: M918T - system: https://civicdb.org/links/variant/ - relation: exactMatch - extensions: - - name: CIViC Molecular Profile Score - value: 139.0 - - name: expressions - value: - - syntax: hgvs.c - value: NM_020975.4:c.2753T>C - - syntax: hgvs.p - value: NP_065681.1:p.Met918Thr - - syntax: hgvs.c - value: ENST00000355710.3:c.2753T>C - - syntax: hgvs.g - value: NC_000010.10:g.43617416T>C - - name: CIViC representative coordinate - value: - chromosome: "10" - ensembl_version: 75 - reference_bases: T - reference_build: GRCh37 - representative_transcript: ENST00000355710.3 - start: 43617416 - stop: 43617416 - type: coordinates - variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: supporting @@ -862,134 +350,6 @@ hasEvidenceLines: - https://civicdb.org/links/evidence/12709 - type: EvidenceLine directionOfEvidenceProvided: supports - targetProposition: # identical to VariantOncogenicityStatement.proposition - type: VariantOncogenicityProposition - objectTumorType: - id: civic.did:15 - conceptType: Disease - name: Medullary Thyroid Carcinoma - mappings: - - coding: - code: DOID:3973 - system: https://disease-ontology.org/?id= - relation: exactMatch - predicate: isOncogenicFor - alleleOriginQualifier: - extensions: - - name: civic_variant_origin - value: SOMATIC - name: somatic - geneContextQualifier: - conceptType: Gene - 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. - id: civic.gid:42 - mappings: - - coding: - code: "5979" - id: ncbigene:5979 - system: https://www.ncbi.nlm.nih.gov/gene/ - relation: exactMatch - name: RET - subjectVariant: - id: civic.mpid:113 - type: CategoricalVariant - description: - RET M918T is the most common somatically acquired mutation in - medullary thyroid cancer (MTC). While there currently are no RET-specific - inhibiting agents, promiscuous kinase inhibitors have seen some success in - treating RET overactivity. Data suggests however, that the M918T mutation - may lead to drug resistance, especially against the VEGFR-inhibitor - motesanib. It has also been suggested that RET M918T leads to more - aggressive MTC with a poorer prognosis. - name: RET M918T - aliases: - - MET918THR - mappings: - - coding: - code: rs74799832 - system: https://www.ncbi.nlm.nih.gov/snp/ - relation: relatedMatch - - coding: - code: CA009082 - system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= - relation: relatedMatch - - coding: - code: "13919" - system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ - relation: relatedMatch - - coding: - id: civic.mpid:113 - code: "113" - system: https://civicdb.org/links/molecular_profile/ - relation: exactMatch - - coding: - code: "113" - extensions: - - name: subtype - value: gene_variant - - name: variant_types - value: - - coding: - code: SO:0001583 - id: civic.variant_type:47 - name: Missense Variant - system: http://www.sequenceontology.org/browser/current_svn/term/ - relation: exactMatch - id: civic.vid:113 - name: M918T - system: https://civicdb.org/links/variant/ - relation: exactMatch - extensions: - - name: CIViC Molecular Profile Score - value: 139.0 - - name: expressions - value: - - syntax: hgvs.c - value: NM_020975.4:c.2753T>C - - syntax: hgvs.p - value: NP_065681.1:p.Met918Thr - - syntax: hgvs.c - value: ENST00000355710.3:c.2753T>C - - syntax: hgvs.g - value: NC_000010.10:g.43617416T>C - - name: CIViC representative coordinate - value: - chromosome: "10" - ensembl_version: 75 - reference_bases: T - reference_build: GRCh37 - representative_transcript: ENST00000355710.3 - start: 43617416 - stop: 43617416 - type: coordinates - variant_bases: C strengthOfEvidenceProvided: primaryCoding: code: supporting From ca47c431dc937d35de7364bba930ae3bf0231cff Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 29 May 2026 12:03:13 -0400 Subject: [PATCH 4/9] add mane select extension --- tests/fixtures/civic-assertion-oncogenicity.yaml | 5 +++++ 1 file changed, 5 insertions(+) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 2669ea6a..2955205a 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -135,6 +135,11 @@ proposition: value: ENST00000355710.3:c.2753T>C - syntax: hgvs.g value: NC_000010.10:g.43617416T>C + - syntax: hgvs.c + value: ENST00000355710.8:c.2753T>C + extensions: + - name: is_mane_select + value: true - name: CIViC representative coordinate value: chromosome: "10" From 4842ff1fe6d79da17d57015433da7d788bc128df Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 29 May 2026 12:34:26 -0400 Subject: [PATCH 5/9] add reported in --- tests/fixtures/civic-assertion-oncogenicity.yaml | 2 ++ 1 file changed, 2 insertions(+) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 2955205a..186c79cb 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -174,6 +174,8 @@ specifiedBy: type: Document methodType: guideline type: Method +reportedIn: + - https://civicdb.org/links/assertion/202 contributions: - activityType: approval.last_reviewed contributor: From 8134d15b239fd1d64af114642e44214c19214091 Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 29 May 2026 12:39:35 -0400 Subject: [PATCH 6/9] sync prop example --- .../civic-proposition-oncogenicity.yaml | 91 ++++++++++++++++++- 1 file changed, 90 insertions(+), 1 deletion(-) diff --git a/tests/fixtures/civic-proposition-oncogenicity.yaml b/tests/fixtures/civic-proposition-oncogenicity.yaml index 4fa2d362..d2aca67e 100644 --- a/tests/fixtures/civic-proposition-oncogenicity.yaml +++ b/tests/fixtures/civic-proposition-oncogenicity.yaml @@ -9,6 +9,49 @@ objectTumorType: system: https://disease-ontology.org/?id= relation: exactMatch predicate: isOncogenicFor +alleleOriginQualifier: + extensions: + - name: civic_variant_origin + value: SOMATIC + name: somatic +geneContextQualifier: + conceptType: Gene + 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. + id: civic.gid:42 + mappings: + - coding: + code: "5979" + id: ncbigene:5979 + system: https://www.ncbi.nlm.nih.gov/gene/ + relation: exactMatch + name: RET subjectVariant: id: civic.mpid:113 type: CategoricalVariant @@ -21,7 +64,7 @@ subjectVariant: aggressive MTC with a poorer prognosis. name: RET M918T aliases: - - MET918THRRS74799832 + - MET918THR mappings: - coding: code: rs74799832 @@ -40,3 +83,49 @@ subjectVariant: code: "113" system: https://civicdb.org/links/molecular_profile/ relation: exactMatch + - coding: + code: "113" + extensions: + - name: subtype + value: gene_variant + - name: variant_types + value: + - coding: + code: SO:0001583 + id: civic.variant_type:47 + name: Missense Variant + system: http://www.sequenceontology.org/browser/current_svn/term/ + relation: exactMatch + id: civic.vid:113 + name: M918T + system: https://civicdb.org/links/variant/ + relation: exactMatch + extensions: + - name: CIViC Molecular Profile Score + value: 139.0 + - name: expressions + value: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + - syntax: hgvs.c + value: ENST00000355710.3:c.2753T>C + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + - syntax: hgvs.c + value: ENST00000355710.8:c.2753T>C + extensions: + - name: is_mane_select + value: true + - name: CIViC representative coordinate + value: + chromosome: "10" + ensembl_version: 75 + reference_bases: T + reference_build: GRCh37 + representative_transcript: ENST00000355710.3 + start: 43617416 + stop: 43617416 + type: coordinates + variant_bases: C From 286939e0b9b2a7db376b766897d81209ad3e456d Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Mon, 1 Jun 2026 14:31:06 -0400 Subject: [PATCH 7/9] civic allele origin ext -> mapping --- tests/fixtures/civic-assertion-oncogenicity.yaml | 8 +++++--- 1 file changed, 5 insertions(+), 3 deletions(-) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 186c79cb..09e43208 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -32,9 +32,11 @@ proposition: relation: exactMatch predicate: isOncogenicFor alleleOriginQualifier: - extensions: - - name: civic_variant_origin - value: SOMATIC + mappings: + - coding: + code: SOMATIC + system: https://civicdb.org + relation: exactMatch name: somatic geneContextQualifier: conceptType: Gene From 69a79b785b53d82bc93675bc478c4747a910b608 Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Mon, 1 Jun 2026 14:35:03 -0400 Subject: [PATCH 8/9] rm citations ext to Statement.reportedIn --- .../civic-assertion-oncogenicity.yaml | 57 +++---------------- 1 file changed, 7 insertions(+), 50 deletions(-) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 09e43208..103963cd 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -178,6 +178,13 @@ specifiedBy: type: Method reportedIn: - https://civicdb.org/links/assertion/202 + - 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 contributions: - activityType: approval.last_reviewed contributor: @@ -230,16 +237,6 @@ hasEvidenceLines: urls: - https://doi.org/10.1016/j.gim.2022.01.001 - https://pubmed.ncbi.nlm.nih.gov/35101336/ - extensions: # These are the same across all evidence lines - - name: citations - value: - - 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 - type: EvidenceLine directionOfEvidenceProvided: supports strengthOfEvidenceProvided: @@ -269,16 +266,6 @@ hasEvidenceLines: urls: - https://doi.org/10.1016/j.gim.2022.01.001 - https://pubmed.ncbi.nlm.nih.gov/35101336/ - extensions: # These are the same across all evidence lines - - name: citations - value: - - 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 - type: EvidenceLine directionOfEvidenceProvided: supports strengthOfEvidenceProvided: @@ -308,16 +295,6 @@ hasEvidenceLines: urls: - https://doi.org/10.1016/j.gim.2022.01.001 - https://pubmed.ncbi.nlm.nih.gov/35101336/ - extensions: # These are the same across all evidence lines - - name: citations - value: - - 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 - type: EvidenceLine directionOfEvidenceProvided: supports strengthOfEvidenceProvided: @@ -347,16 +324,6 @@ hasEvidenceLines: urls: - https://doi.org/10.1016/j.gim.2022.01.001 - https://pubmed.ncbi.nlm.nih.gov/35101336/ - extensions: # These are the same across all evidence lines - - name: citations - value: - - 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 - type: EvidenceLine directionOfEvidenceProvided: supports strengthOfEvidenceProvided: @@ -386,13 +353,3 @@ hasEvidenceLines: urls: - https://doi.org/10.1016/j.gim.2022.01.001 - https://pubmed.ncbi.nlm.nih.gov/35101336/ - extensions: # These are the same across all evidence lines - - name: citations - value: - - 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 From fff6f3015eed9105325faf3d887fdc076bf16743 Mon Sep 17 00:00:00 2001 From: Kori Kuzma Date: Fri, 5 Jun 2026 15:54:00 -0400 Subject: [PATCH 9/9] apply civicpy mp changes * members, constraints, ids on mappings --- .../civic-assertion-oncogenicity.yaml | 100 +++++++++++++++--- 1 file changed, 87 insertions(+), 13 deletions(-) diff --git a/tests/fixtures/civic-assertion-oncogenicity.yaml b/tests/fixtures/civic-assertion-oncogenicity.yaml index 103963cd..ecf78941 100644 --- a/tests/fixtures/civic-assertion-oncogenicity.yaml +++ b/tests/fixtures/civic-assertion-oncogenicity.yaml @@ -89,22 +89,81 @@ proposition: name: RET M918T aliases: - MET918THR + constraints: + - allele: + digest: hEybNB_CeKflfFhT5AKOU5i1lgZPP-aS + expressions: + - syntax: hgvs.p + value: NP_065681.1:p.Met918Thr + id: ga4gh:VA.hEybNB_CeKflfFhT5AKOU5i1lgZPP-aS + location: + digest: oIeqSfOEuqO7KNOPt8YUIa9vo1f6yMao + end: 918 + id: ga4gh:SL.oIeqSfOEuqO7KNOPt8YUIa9vo1f6yMao + sequence: M + sequenceReference: + refgetAccession: SQ.jMu9-ItXSycQsm4hyABeW_UfSNRXRVnl + type: SequenceReference + start: 917 + type: SequenceLocation + name: RET M918T + state: + sequence: T + type: LiteralSequenceExpression + type: Allele + relations: + - primaryCoding: + code: liftover_to + system: ga4gh-gks-term:allele-relation + - primaryCoding: + code: translation_of + system: http://www.sequenceontology.org + type: DefiningAlleleConstraint + members: + - digest: TZBjEPHhLRYxssQopcOQLWEBQrwzhH3T + expressions: + - syntax: hgvs.c + value: NM_020975.4:c.2753T>C + id: ga4gh:VA.TZBjEPHhLRYxssQopcOQLWEBQrwzhH3T + location: + digest: LD_QnJ8V1MR3stLat01acwyO4fWrUGco + end: 2943 + id: ga4gh:SL.LD_QnJ8V1MR3stLat01acwyO4fWrUGco + sequence: T + sequenceReference: + refgetAccession: SQ.jHlgYyFWJThVNL_o5UXEBwcQVNEPc62c + type: SequenceReference + start: 2942 + type: SequenceLocation + name: NM_020975.4:c.2753T>C + state: + sequence: C + type: LiteralSequenceExpression + type: Allele + - digest: ON-Q17mJBYx3unmQ8GiqllzEphxR-Fie + expressions: + - syntax: hgvs.g + value: NC_000010.10:g.43617416T>C + id: ga4gh:VA.ON-Q17mJBYx3unmQ8GiqllzEphxR-Fie + location: + digest: wIzpygPWdaZBkoKcIg461KaERW7XfyZS + end: 43121968 + id: ga4gh:SL.wIzpygPWdaZBkoKcIg461KaERW7XfyZS + sequence: T + sequenceReference: + refgetAccession: SQ.ss8r_wB0-b9r44TQTMmVTI92884QvBiB + type: SequenceReference + start: 43121967 + type: SequenceLocation + name: NC_000010.10:g.43617416T>C + state: + sequence: C + type: LiteralSequenceExpression + type: Allele mappings: - coding: - code: rs74799832 - system: https://www.ncbi.nlm.nih.gov/snp/ - relation: relatedMatch - - coding: - code: CA009082 - system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= - relation: relatedMatch - - coding: - code: "13919" - system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ - relation: relatedMatch - - coding: - id: civic.mpid:113 code: "113" + id: civic.mpid:113 system: https://civicdb.org/links/molecular_profile/ relation: exactMatch - coding: @@ -124,6 +183,21 @@ proposition: name: M918T system: https://civicdb.org/links/variant/ relation: exactMatch + - coding: + code: CA009082 + id: clingen.allele:CA009082 + system: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid= + relation: relatedMatch + - coding: + code: "13919" + id: clinvar:13919 + system: https://www.ncbi.nlm.nih.gov/clinvar/variation/ + relation: relatedMatch + - coding: + code: rs74799832 + id: dbsnp:rs74799832 + system: https://www.ncbi.nlm.nih.gov/snp/ + relation: relatedMatch extensions: - name: CIViC Molecular Profile Score value: 139.0