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| { | |
| "metadata": { | |
| "description": "Curated ClinVar SNP variants for OpenEnv Variant Classification Environment", | |
| "source": "ClinVar (NCBI) + gnomAD population frequencies", | |
| "genome_build": "GRCh38", | |
| "variant_type": "single_nucleotide_variant (SNP)", | |
| "version": "v2-patched", | |
| "tiers": { | |
| "easy": "Benign or Likely Benign \u2014 clear benign signals (high AF, no disease association)", | |
| "medium": "Pathogenic or Likely Pathogenic \u2014 clear pathogenic signals (loss-of-function, expert reviewed)", | |
| "hard": "Uncertain Significance \u2014 missense variants with insufficient evidence" | |
| }, | |
| "total_variants": 24, | |
| "variants_per_tier": { | |
| "easy": 8, | |
| "medium": 8, | |
| "hard": 8 | |
| }, | |
| "patch_notes": "Manual patches: corrected disease mismatches (VHL, TSC1, RET, MSH2), strengthened hard tier evidence snippets to include contradictory signals, improved benign snippet logic for low-AF easy variants." | |
| }, | |
| "variants": { | |
| "easy": [ | |
| { | |
| "variant_id": "1121942", | |
| "chromosome": "3", | |
| "position": 10052380, | |
| "ref": "T", | |
| "alt": "A", | |
| "gene": "VHL", | |
| "hgvs": "NC_000003.12:g.10052380T>A", | |
| "consequence": "intron_variant", | |
| "disease": "Von Hippel-Lindau disease", | |
| "classification": "Likely_benign", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs548887691", | |
| "population_frequency": 5.252859525404142e-05, | |
| "evidence_snippets": [ | |
| "VHL is a well-characterized tumor suppressor gene associated with Von Hippel-Lindau disease, a hereditary condition predisposing to clear cell renal carcinoma, hemangioblastomas, and pheochromocytoma. Variants in VHL are routinely assessed in clinical genetic testing.", | |
| "This intronic variant falls outside the protein-coding region of VHL. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000053). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant has been observed in population controls and no functional studies have demonstrated disruption of VHL protein function. The intronic location and available evidence support a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "1549247", | |
| "chromosome": "3", | |
| "position": 38550327, | |
| "ref": "G", | |
| "alt": "A", | |
| "gene": "SCN5A", | |
| "hgvs": "NC_000003.12:g.38550327G>A", | |
| "consequence": "synonymous_variant", | |
| "disease": "Cardiovascular phenotype", | |
| "classification": "Likely_benign", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs766459103", | |
| "population_frequency": 1.4614263813767513e-06, | |
| "evidence_snippets": [ | |
| "SCN5A is a well-characterized disease gene associated with Brugada syndrome and Long QT syndrome type 3. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This is a synonymous variant (no amino acid change) \u2014 the amino acid sequence is unchanged. Synonymous variants are generally considered less likely to be pathogenic unless they affect splicing regulatory elements.", | |
| "This variant has a very low population allele frequency in gnomAD (AF=0.000001). However, it is a synonymous variant causing no amino acid change, which is itself strong evidence against pathogenicity independent of frequency.", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on SCN5A protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "365386", | |
| "chromosome": "9", | |
| "position": 132891472, | |
| "ref": "A", | |
| "alt": "G", | |
| "gene": "TSC1", | |
| "hgvs": "NC_000009.12:g.132891472A>G", | |
| "consequence": "3_prime_UTR_variant", | |
| "disease": "Isolated focal cortical dysplasia type II", | |
| "classification": "Benign", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs79470094", | |
| "population_frequency": 0.019410019429711704, | |
| "evidence_snippets": [ | |
| "TSC1 is a well-characterized disease gene associated with Tuberous Sclerosis Complex. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This 3' UTR variant falls outside the protein-coding region of TSC1. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant has a high population allele frequency of 0.0194 (1.94%) in gnomAD, consistent with a common polymorphism. High population frequency is strong evidence against pathogenicity (BA1 criterion).", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on TSC1 protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "1178859", | |
| "chromosome": "3", | |
| "position": 10141318, | |
| "ref": "G", | |
| "alt": "C", | |
| "gene": "VHL", | |
| "hgvs": "NC_000003.12:g.10141318G>C", | |
| "consequence": null, | |
| "disease": "Von Hippel-Lindau disease", | |
| "classification": "Benign", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs10433558", | |
| "population_frequency": 0.23617010085602705, | |
| "evidence_snippets": [ | |
| "VHL is a well-characterized tumor suppressor gene associated with Von Hippel-Lindau disease. Variants in VHL are routinely assessed in clinical genetic testing.", | |
| "The molecular consequence of this variant within VHL has not been definitively annotated. Interpretation relies primarily on population frequency data, segregation studies, and gene-level disease association evidence.", | |
| "This variant has a high population allele frequency of 0.2362 (23.62%) in gnomAD, consistent with a common polymorphism. High population frequency is strong evidence against pathogenicity (BA1 criterion).", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on VHL protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "922754", | |
| "chromosome": "3", | |
| "position": 38550315, | |
| "ref": "C", | |
| "alt": "T", | |
| "gene": "SCN5A", | |
| "hgvs": "NC_000003.12:g.38550315C>T", | |
| "consequence": "3_prime_UTR_variant", | |
| "disease": "Cardiac arrhythmia", | |
| "classification": "Likely_benign", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs776980213", | |
| "population_frequency": 5.256518082422203e-05, | |
| "evidence_snippets": [ | |
| "SCN5A is a well-characterized disease gene associated with Brugada syndrome and Long QT syndrome type 3. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This 3' UTR variant falls outside the protein-coding region of SCN5A. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000053). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on SCN5A protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "767548", | |
| "chromosome": "10", | |
| "position": 43077264, | |
| "ref": "G", | |
| "alt": "A", | |
| "gene": "RET", | |
| "hgvs": "NC_000010.11:g.43077264G>A", | |
| "consequence": "synonymous_variant", | |
| "disease": "Multiple Endocrine Neoplasia type 2", | |
| "classification": "Likely_benign", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs1243883489", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "RET is a proto-oncogene associated with Multiple Endocrine Neoplasia type 2 (MEN2) and Hirschsprung disease. Gain-of-function variants cause MEN2; loss-of-function variants cause Hirschsprung disease.", | |
| "This is a synonymous variant (no amino acid change) \u2014 the amino acid sequence is unchanged. Synonymous variants are generally considered less likely to be pathogenic unless they affect splicing regulatory elements.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on RET protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "89588", | |
| "chromosome": "3", | |
| "position": 36993279, | |
| "ref": "C", | |
| "alt": "G", | |
| "gene": "MLH1", | |
| "hgvs": "NC_000003.12:g.36993279C>G", | |
| "consequence": null, | |
| "disease": "Hereditary nonpolyposis colorectal neoplasms", | |
| "classification": "Likely_benign", | |
| "review_status": "reviewed_by_expert_panel", | |
| "rs_id": "rs35032294", | |
| "population_frequency": 0.005335906119555801, | |
| "evidence_snippets": [ | |
| "MLH1 is a well-characterized disease gene associated with Lynch syndrome (hereditary colorectal cancer). Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "The molecular consequence of this variant within MLH1 has not been definitively annotated. Interpretation relies primarily on population frequency data, segregation studies, and gene-level disease association evidence.", | |
| "This variant has a moderate population allele frequency of 0.00534 in gnomAD. Intermediate frequencies require careful interpretation alongside functional and clinical evidence \u2014 neither strongly supporting nor refuting pathogenicity.", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on MLH1 protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| }, | |
| { | |
| "variant_id": "818101", | |
| "chromosome": "7", | |
| "position": 117479129, | |
| "ref": "T", | |
| "alt": "G", | |
| "gene": "CFTR", | |
| "hgvs": "NC_000007.14:g.117479129T>G", | |
| "consequence": null, | |
| "disease": "Cystic fibrosis", | |
| "classification": "Benign", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs4148682", | |
| "population_frequency": 0.1115332535790816, | |
| "evidence_snippets": [ | |
| "CFTR is a well-characterized disease gene associated with Cystic Fibrosis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "No molecular consequence annotation is available for this specific variant position in CFTR. However, given its high population frequency, it is considered a common polymorphism unlikely to affect CFTR protein function.", | |
| "This variant has a high population allele frequency of 0.1115 (11.15%) in gnomAD, consistent with a common polymorphism. High population frequency is strong evidence against pathogenicity (BA1 criterion).", | |
| "This variant has been observed in multiple unaffected population controls. No functional studies have demonstrated a deleterious effect on CFTR protein function, supporting a benign classification." | |
| ], | |
| "tier": "easy" | |
| } | |
| ], | |
| "medium": [ | |
| { | |
| "variant_id": "91055", | |
| "chromosome": "2", | |
| "position": 47403219, | |
| "ref": "C", | |
| "alt": "T", | |
| "gene": "MSH2", | |
| "hgvs": "NC_000002.12:g.47403219C>T", | |
| "consequence": "nonsense", | |
| "disease": "Hereditary nonpolyposis colorectal neoplasms", | |
| "classification": "Pathogenic", | |
| "review_status": "reviewed_by_expert_panel", | |
| "rs_id": "rs63751099", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "MSH2 is a well-characterized disease gene associated with Lynch syndrome (hereditary colorectal cancer). Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant introduces a premature stop codon (nonsense variant (premature stop codon)), likely resulting in a truncated or absent MSH2 protein product. Loss-of-function variants in MSH2 are frequently pathogenic.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "Published functional studies and clinical case reports have documented this or closely related variants in MSH2 among individuals diagnosed with Hereditary nonpolyposis colorectal neoplasms. Multiple submitting laboratories classify this variant as disease-causing." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "91225", | |
| "chromosome": "2", | |
| "position": 47403273, | |
| "ref": "G", | |
| "alt": "T", | |
| "gene": "MSH2", | |
| "hgvs": "NC_000002.12:g.47403273G>T", | |
| "consequence": "nonsense", | |
| "disease": "Lynch syndrome", | |
| "classification": "Pathogenic", | |
| "review_status": "reviewed_by_expert_panel", | |
| "rs_id": "rs63751246", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "MSH2 is a well-characterized disease gene associated with Lynch syndrome (hereditary colorectal cancer). Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant introduces a premature stop codon (nonsense variant (premature stop codon)), likely resulting in a truncated or absent MSH2 protein product. Loss-of-function variants in MSH2 are frequently pathogenic.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "Published functional studies and clinical reports have documented this MSH2 nonsense variant in individuals diagnosed with Lynch syndrome. Multiple submitting laboratories classify it as pathogenic." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "2561023", | |
| "chromosome": "3", | |
| "position": 10142035, | |
| "ref": "T", | |
| "alt": "G", | |
| "gene": "VHL", | |
| "hgvs": "NC_000003.12:g.10142035T>G", | |
| "consequence": "missense_variant", | |
| "disease": "Von Hippel-Lindau disease", | |
| "classification": "Likely_pathogenic", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs104893827", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "VHL is a well-characterized tumor suppressor gene associated with Von Hippel-Lindau disease. Missense variants in VHL are a common mechanism of disease, particularly those affecting protein folding or HIF-1alpha binding.", | |
| "This variant results in a missense variant (amino acid change), altering the encoded amino acid at this position. Missense variants in VHL require careful evaluation of their functional impact on protein structure and activity.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "This missense variant in VHL has been reported in individuals with Von Hippel-Lindau disease. Functional evidence suggests disruption of normal VHL protein interactions." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "68002", | |
| "chromosome": "3", | |
| "position": 38550748, | |
| "ref": "A", | |
| "alt": "G", | |
| "gene": "SCN5A", | |
| "hgvs": "NC_000003.12:g.38550748A>G", | |
| "consequence": "missense_variant", | |
| "disease": "Atrial fibrillation", | |
| "classification": "Likely_pathogenic", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs199473324", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "SCN5A is a well-characterized disease gene associated with Brugada syndrome and Long QT syndrome type 3. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant results in a missense variant (amino acid change), altering the encoded amino acid at this position. Missense variants in SCN5A require careful evaluation of their functional impact on protein structure and activity.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "Published functional studies and clinical case reports have documented this or closely related variants in SCN5A among individuals diagnosed with Atrial fibrillation. Multiple submitting laboratories classify this variant as disease-causing." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "2584327", | |
| "chromosome": "5", | |
| "position": 112754908, | |
| "ref": "T", | |
| "alt": "G", | |
| "gene": "APC", | |
| "hgvs": "NC_000005.10:g.112754908T>G", | |
| "consequence": "nonsense", | |
| "disease": "Familial adenomatous polyposis 1", | |
| "classification": "Pathogenic", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs786202301", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "APC is a well-characterized disease gene associated with Familial Adenomatous Polyposis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant introduces a premature stop codon (nonsense variant (premature stop codon)), likely resulting in a truncated or absent APC protein product. Loss-of-function variants in APC are frequently pathogenic.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "Published functional studies and clinical case reports have documented this or closely related variants in APC among individuals diagnosed with Familial adenomatous polyposis 1. Multiple submitting laboratories classify this variant as disease-causing." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "53622", | |
| "chromosome": "7", | |
| "position": 117480096, | |
| "ref": "T", | |
| "alt": "C", | |
| "gene": "CFTR", | |
| "hgvs": "NC_000007.14:g.117480096T>C", | |
| "consequence": "initiator_codon_variant", | |
| "disease": "CFTR-related disorder", | |
| "classification": "Pathogenic", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs397508476", | |
| "population_frequency": 5.472981940527841e-06, | |
| "evidence_snippets": [ | |
| "CFTR is a well-characterized disease gene associated with Cystic Fibrosis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant is annotated as a initiator codon variant in CFTR. Further functional characterization may be needed to assess its impact.", | |
| "This variant is rare in the general population (gnomAD AF=0.000005). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "Published functional studies and clinical case reports have documented this or closely related variants in CFTR among individuals diagnosed with CFTR-related disorder. Multiple submitting laboratories classify this variant as disease-causing." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "1796488", | |
| "chromosome": "9", | |
| "position": 132897335, | |
| "ref": "G", | |
| "alt": "A", | |
| "gene": "TSC1", | |
| "hgvs": "NC_000009.12:g.132897335G>A", | |
| "consequence": "nonsense", | |
| "disease": "Tuberous Sclerosis Complex", | |
| "classification": "Pathogenic", | |
| "review_status": "criteria_provided, multiple_submitters, no_conflicts", | |
| "rs_id": "rs2131628564", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "TSC1 encodes hamartin, a tumor suppressor that forms a complex with TSC2. Pathogenic variants in TSC1 cause Tuberous Sclerosis Complex (TSC), characterized by benign tumors (hamartomas) in multiple organs including brain, kidneys, and skin.", | |
| "This variant introduces a premature stop codon (nonsense variant (premature stop codon)), likely resulting in a truncated or absent TSC1 protein product. Loss-of-function variants in TSC1 are frequently pathogenic.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "This nonsense variant in TSC1 is expected to result in hamartin loss-of-function via nonsense-mediated decay. Loss-of-function variants in TSC1 are a well-established cause of Tuberous Sclerosis Complex." | |
| ], | |
| "tier": "medium" | |
| }, | |
| { | |
| "variant_id": "4756584", | |
| "chromosome": "3", | |
| "position": 38550937, | |
| "ref": "G", | |
| "alt": "T", | |
| "gene": "SCN5A", | |
| "hgvs": "NC_000003.12:g.38550937G>T", | |
| "consequence": "nonsense", | |
| "disease": "Cardiac arrhythmia", | |
| "classification": "Likely_pathogenic", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": null, | |
| "population_frequency": 0.0, | |
| "evidence_snippets": [ | |
| "SCN5A is a well-characterized disease gene associated with Brugada syndrome and Long QT syndrome type 3. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant introduces a premature stop codon (nonsense variant (premature stop codon)), likely resulting in a truncated or absent SCN5A protein product. Loss-of-function variants in SCN5A are frequently pathogenic.", | |
| "This variant has an allele frequency of 0 in gnomAD (observed 0 times). Complete absence from population databases supports but does not confirm pathogenicity.", | |
| "Published functional studies and clinical case reports have documented this or closely related variants in SCN5A among individuals diagnosed with Cardiac arrhythmia. Multiple submitting laboratories classify this variant as disease-causing." | |
| ], | |
| "tier": "medium" | |
| } | |
| ], | |
| "hard": [ | |
| { | |
| "variant_id": "1744639", | |
| "chromosome": "2", | |
| "position": 47403074, | |
| "ref": "T", | |
| "alt": "G", | |
| "gene": "MSH2", | |
| "hgvs": "NC_000002.12:g.47403074T>G", | |
| "consequence": "5_prime_UTR_variant", | |
| "disease": "Hereditary cancer-predisposing syndrome", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs2303425", | |
| "population_frequency": 4.913651562181661e-05, | |
| "evidence_snippets": [ | |
| "MSH2 is a well-characterized disease gene associated with Lynch syndrome (hereditary colorectal cancer). Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This 5' UTR variant falls outside the protein-coding region of MSH2. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000049). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant presents conflicting signals: the 5 prime UTR variant location in MSH2 is outside the protein-coding region, generally supporting a benign interpretation. However, MSH2 is a high-confidence disease gene for Hereditary cancer-predisposing syndrome, and regulatory region variants have occasionally been reported to affect gene expression. Insufficient functional data exists to resolve this uncertainty, warranting a VUS classification." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "186689", | |
| "chromosome": "2", | |
| "position": 47403078, | |
| "ref": "G", | |
| "alt": "A", | |
| "gene": "MSH2", | |
| "hgvs": "NC_000002.12:g.47403078G>A", | |
| "consequence": "5_prime_UTR_variant", | |
| "disease": "Hereditary cancer-predisposing syndrome", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs786203146", | |
| "population_frequency": 1.1118350392588952e-06, | |
| "evidence_snippets": [ | |
| "MSH2 is a well-characterized disease gene associated with Lynch syndrome (hereditary colorectal cancer). Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This 5' UTR variant falls outside the protein-coding region of MSH2. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000001). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant presents conflicting signals: the 5 prime UTR variant location in MSH2 is outside the protein-coding region, generally supporting a benign interpretation. However, MSH2 is a high-confidence disease gene for Hereditary cancer-predisposing syndrome, and regulatory region variants have occasionally been reported to affect gene expression. Insufficient functional data exists to resolve this uncertainty, warranting a VUS classification." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "2183337", | |
| "chromosome": "3", | |
| "position": 36993071, | |
| "ref": "T", | |
| "alt": "C", | |
| "gene": "MLH1", | |
| "hgvs": "NC_000003.12:g.36993071T>C", | |
| "consequence": "missense_variant", | |
| "disease": "Hereditary nonpolyposis colorectal neoplasms", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs746415556", | |
| "population_frequency": null, | |
| "evidence_snippets": [ | |
| "MLH1 is a well-characterized disease gene associated with Lynch syndrome (hereditary colorectal cancer). Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This variant results in a missense variant (amino acid change), altering the encoded amino acid at this position. Missense variants in MLH1 require careful evaluation of their functional impact on protein structure and activity.", | |
| "This variant was not observed in gnomAD population databases or frequency data is unavailable. Absence from population databases may reflect extreme rarity but should be interpreted cautiously.", | |
| "Current evidence for this MLH1 missense variant is insufficient for definitive classification. Computational prediction tools show conflicting results: some predict deleterious impact while others suggest tolerated. No functional assay data or well-powered segregation studies are available for this specific position. It remains a VUS pending further evidence." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "650293", | |
| "chromosome": "5", | |
| "position": 112707498, | |
| "ref": "G", | |
| "alt": "A", | |
| "gene": "APC", | |
| "hgvs": "NC_000005.10:g.112707498G>A", | |
| "consequence": "non-coding_transcript_variant", | |
| "disease": "Familial adenomatous polyposis 1", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs1381567636", | |
| "population_frequency": 6.567195544814543e-06, | |
| "evidence_snippets": [ | |
| "APC is a well-characterized disease gene associated with Familial Adenomatous Polyposis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This non-coding transcript variant falls outside the protein-coding region of APC. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000007). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant presents conflicting signals: the non-coding transcript variant location in APC is outside the protein-coding region, generally supporting a benign interpretation. However, APC is a high-confidence disease gene for Familial adenomatous polyposis 1, and regulatory region variants have occasionally been reported to affect gene expression. Insufficient functional data exists to resolve this uncertainty, warranting a VUS classification." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "2417404", | |
| "chromosome": "5", | |
| "position": 112707499, | |
| "ref": "C", | |
| "alt": "A", | |
| "gene": "APC", | |
| "hgvs": "NC_000005.10:g.112707499C>A", | |
| "consequence": "non-coding_transcript_variant", | |
| "disease": "Familial adenomatous polyposis 1", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs1178835678", | |
| "population_frequency": 0.0, | |
| "evidence_snippets": [ | |
| "APC is a well-characterized disease gene associated with Familial Adenomatous Polyposis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This non-coding transcript variant falls outside the protein-coding region of APC. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant has an allele frequency of 0 in gnomAD (observed 0 times). Complete absence from population databases supports but does not confirm pathogenicity.", | |
| "This variant presents conflicting signals: the non-coding transcript variant location in APC is outside the protein-coding region, generally supporting a benign interpretation. However, APC is a high-confidence disease gene for Familial adenomatous polyposis 1, and regulatory region variants have occasionally been reported to affect gene expression. Insufficient functional data exists to resolve this uncertainty, warranting a VUS classification." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "1379956", | |
| "chromosome": "7", | |
| "position": 117480087, | |
| "ref": "G", | |
| "alt": "A", | |
| "gene": "CFTR", | |
| "hgvs": "NC_000007.14:g.117480087G>A", | |
| "consequence": "5_prime_UTR_variant", | |
| "disease": "Cystic fibrosis", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs1800501", | |
| "population_frequency": 6.84127422837268e-07, | |
| "evidence_snippets": [ | |
| "CFTR is a well-characterized disease gene associated with Cystic Fibrosis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This 5' UTR variant falls outside the protein-coding region of CFTR. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000001). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant presents conflicting signals: the 5 prime UTR variant location in CFTR is outside the protein-coding region, generally supporting a benign interpretation. However, CFTR is a high-confidence disease gene for Cystic fibrosis, and regulatory region variants have occasionally been reported to affect gene expression. Insufficient functional data exists to resolve this uncertainty, warranting a VUS classification." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "2169688", | |
| "chromosome": "7", | |
| "position": 117480088, | |
| "ref": "A", | |
| "alt": "T", | |
| "gene": "CFTR", | |
| "hgvs": "NC_000007.14:g.117480088A>T", | |
| "consequence": "5_prime_UTR_variant", | |
| "disease": "Cystic fibrosis", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs1797976459", | |
| "population_frequency": 6.841077661281826e-07, | |
| "evidence_snippets": [ | |
| "CFTR is a well-characterized disease gene associated with Cystic Fibrosis. Variants in this gene are routinely assessed in clinical genetic testing.", | |
| "This 5' UTR variant falls outside the protein-coding region of CFTR. Non-coding variants generally require additional functional evidence to support pathogenicity classification.", | |
| "This variant is rare in the general population (gnomAD AF=0.000001). Low frequency is consistent with a potentially pathogenic variant, though rarity alone is insufficient to classify a variant as disease-causing.", | |
| "This variant presents conflicting signals: the 5 prime UTR variant location in CFTR is outside the protein-coding region, generally supporting a benign interpretation. However, CFTR is a high-confidence disease gene for Cystic fibrosis, and regulatory region variants have occasionally been reported to affect gene expression. Insufficient functional data exists to resolve this uncertainty, warranting a VUS classification." | |
| ], | |
| "tier": "hard" | |
| }, | |
| { | |
| "variant_id": "914228", | |
| "chromosome": "9", | |
| "position": 132891697, | |
| "ref": "T", | |
| "alt": "C", | |
| "gene": "TSC1", | |
| "hgvs": "NC_000009.12:g.132891697T>C", | |
| "consequence": "3_prime_UTR_variant", | |
| "disease": "Tuberous Sclerosis Complex", | |
| "classification": "Uncertain_significance", | |
| "review_status": "criteria_provided, single_submitter", | |
| "rs_id": "rs1036825417", | |
| "population_frequency": 3.940886699507389e-05, | |
| "evidence_snippets": [ | |
| "TSC1 encodes hamartin, a tumor suppressor associated with Tuberous Sclerosis Complex. The 3' UTR region of TSC1 contains regulatory elements that influence mRNA stability and expression levels.", | |
| "This 3' UTR variant does not alter the TSC1 protein sequence directly, but could potentially affect mRNA stability, translational efficiency, or microRNA binding sites. The functional significance of this specific position has not been experimentally validated.", | |
| "This variant has a low population frequency (AF=0.000039 in gnomAD), which is consistent with either a rare benign polymorphism or a low-penetrance disease variant. Frequency alone cannot distinguish between these possibilities for 3' UTR variants.", | |
| "Current evidence for this variant in TSC1 is insufficient for definitive classification. While TSC1 is associated with Isolated focal cortical dysplasia type II, no functional studies or well-powered segregation analyses have been published for this specific position. It remains a variant of uncertain significance pending further data." | |
| ], | |
| "tier": "hard" | |
| } | |
| ] | |
| } | |
| } |