import { assert } from 'chai'; import _ from 'lodash'; import { VariantAnnotation } from 'genome-nexus-ts-api-client'; import { Mutation } from '../model/Mutation'; import { annotateMutation, annotateMutations, indexAnnotationsByGenomicLocation, resolveMissingProteinPositions, } from './MutationAnnotator'; describe('MutationAnnotator', () => { const variantAnnotations = [ { variant: 'X:g.66937331T>A', originalVariantQuery: 'X,66937331,66937331,T,A', colocatedVariants: [ { dbSnpId: 'COSM73703', }, ], id: 'X:g.66937331T>A', assembly_name: 'GRCh37', seq_region_name: 'X', start: 66937331, end: 66937331, allele_string: 'T/A', strand: 1, most_severe_consequence: 'missense_variant', transcript_consequences: [ { transcript_id: 'ENST00000374690', hgvsp: 'ENSP00000363822.3:p.Leu729Ile', hgvsc: 'ENST00000374690.3:c.2185T>A', variant_allele: 'A', codons: 'Tta/Ata', protein_id: 'ENSP00000363822', protein_start: 729, protein_end: 729, gene_symbol: 'AR', gene_id: 'ENSG00000169083', amino_acids: 'L/I', hgnc_id: 644, canonical: '1', polyphen_score: 0.999, polyphen_prediction: 'probably_damaging', sift_score: 0.01, sift_prediction: 'deleterious', refseq_transcript_ids: ['NM_000044.3'], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000396043', hgvsp: 'ENSP00000379358.2:p.Leu197Ile', hgvsc: 'ENST00000396043.2:c.589T>A', variant_allele: 'A', codons: 'Tta/Ata', protein_id: 'ENSP00000379358', protein_start: 197, protein_end: 197, gene_symbol: 'AR', gene_id: 'ENSG00000169083', amino_acids: 'L/I', hgnc_id: 644, polyphen_score: 0.867, polyphen_prediction: 'possibly_damaging', sift_score: 0.02, sift_prediction: 'deleterious', refseq_transcript_ids: ['NM_001011645.2'], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000396044', hgvsc: 'ENST00000396044.3:c.2173+5800T>A', variant_allele: 'A', protein_id: 'ENSP00000379359', gene_symbol: 'AR', gene_id: 'ENSG00000169083', hgnc_id: 644, consequence_terms: ['intron_variant'], }, ], annotation_summary: { variant: 'X:g.66937331T>A', genomicLocation: { chromosome: 'X', start: 66937331, end: 66937331, referenceAllele: 'T', variantAllele: 'A', }, strandSign: '+', variantType: 'SNP', assemblyName: 'GRCh37', canonicalTranscriptId: 'ENST00000374690', transcriptConsequences: [ { transcriptId: 'ENST00000374690', codonChange: 'Tta/Ata', entrezGeneId: '367', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'AR', hgvspShort: 'p.L729I', hgvsp: 'p.Leu729Ile', hgvsc: 'ENST00000374690.3:c.2185T>A', proteinPosition: { start: 729, end: 729, }, refSeq: 'NM_000044.3', variantClassification: 'Missense_Mutation', }, ], transcriptConsequenceSummaries: [ { transcriptId: 'ENST00000374690', codonChange: 'Tta/Ata', entrezGeneId: '367', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'AR', hgvspShort: 'p.L729I', hgvsp: 'p.Leu729Ile', hgvsc: 'ENST00000374690.3:c.2185T>A', proteinPosition: { start: 729, end: 729, }, refSeq: 'NM_000044.3', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000396043', codonChange: 'Tta/Ata', entrezGeneId: '367', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'AR', hgvspShort: 'p.L197I', hgvsp: 'p.Leu197Ile', hgvsc: 'ENST00000396043.2:c.589T>A', proteinPosition: { start: 197, end: 197, }, refSeq: 'NM_001011645.2', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000396044', entrezGeneId: '367', consequenceTerms: 'intron_variant', hugoGeneSymbol: 'AR', hgvspShort: '*725*', hgvsc: 'ENST00000396044.3:c.2173+5800T>A', variantClassification: 'Intron', }, ], transcriptConsequenceSummary: { transcriptId: 'ENST00000374690', codonChange: 'Tta/Ata', entrezGeneId: '367', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'AR', hgvspShort: 'p.L729I', hgvsp: 'p.Leu729Ile', hgvsc: 'ENST00000374690.3:c.2185T>A', proteinPosition: { start: 729, end: 729, }, refSeq: 'NM_000044.3', variantClassification: 'Missense_Mutation', }, }, }, { variant: '17:g.41242962_41242963insGA', originalVariantQuery: '17,41242962,41242963,-,GA', colocatedVariants: [ { gnomad_nfe_maf: '9.314E-6', gnomad_nfe_allele: 'A', gnomad_afr_maf: '0', gnomad_afr_allele: 'A', gnomad_eas_maf: '0', gnomad_eas_allele: 'A', dbSnpId: 'rs80357742', }, ], id: '17:g.41242962_41242963insGA', assembly_name: 'GRCh37', seq_region_name: '17', start: 41242963, end: 41242962, allele_string: '-/GA', strand: 1, most_severe_consequence: 'frameshift_variant', transcript_consequences: [ { transcript_id: 'ENST00000309486', hgvsp: 'ENSP00000310938.4:p.Gln1099LeufsTer11', hgvsc: 'ENST00000309486.4:c.3294_3295dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000310938', protein_start: 1099, protein_end: 1099, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, refseq_transcript_ids: ['NM_007297.3'], consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000346315', hgvsp: 'ENSP00000246907.4:p.Gln1395LeufsTer11', hgvsc: 'ENST00000346315.3:c.4182_4183dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000246907', protein_start: 1395, protein_end: 1395, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000351666', hgvsp: 'ENSP00000338007.3:p.Gln212LeufsTer11', hgvsc: 'ENST00000351666.3:c.633_634dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000338007', protein_start: 212, protein_end: 212, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000352993', hgvsp: 'ENSP00000312236.5:p.Gln253LeufsTer11', hgvsc: 'ENST00000352993.3:c.756_757dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000312236', protein_start: 253, protein_end: 253, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000354071', hgvsp: 'ENSP00000326002.6:p.Gln1395LeufsTer11', hgvsc: 'ENST00000354071.3:c.4182_4183dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000326002', protein_start: 1395, protein_end: 1395, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000357654', hgvsp: 'ENSP00000350283.3:p.Gln1395LeufsTer11', hgvsc: 'ENST00000357654.3:c.4182_4183dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000350283', protein_start: 1395, protein_end: 1395, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, canonical: '1', refseq_transcript_ids: ['NM_007294.3'], consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000412061', variant_allele: 'GA', protein_id: 'ENSP00000397145', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000461221', hgvsc: 'ENST00000461221.1:c.*3965_*3966dup', variant_allele: 'GA', protein_id: 'ENSP00000418548', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: [ 'splice_region_variant', '3_prime_UTR_variant', 'NMD_transcript_variant', ], }, { transcript_id: 'ENST00000461574', hgvsp: 'ENSP00000417241.1:p.Gln160LeufsTer11', hgvsc: 'ENST00000461574.1:c.476_477dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000417241', protein_start: 160, protein_end: 160, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000467274', variant_allele: 'GA', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000468300', hgvsp: 'ENSP00000417148.1:p.Gln292LeufsTer11', hgvsc: 'ENST00000468300.1:c.873_874dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000417148', protein_start: 292, protein_end: 292, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, refseq_transcript_ids: ['NM_007299.3'], consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000470026', variant_allele: 'GA', protein_id: 'ENSP00000419274', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000471181', hgvsp: 'ENSP00000418960.2:p.Gln1395LeufsTer11', hgvsc: 'ENST00000471181.2:c.4182_4183dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000418960', protein_start: 1395, protein_end: 1395, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, refseq_transcript_ids: ['NM_007300.3'], consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000473961', variant_allele: 'GA', protein_id: 'ENSP00000420201', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000476777', variant_allele: 'GA', protein_id: 'ENSP00000417554', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000477152', variant_allele: 'GA', protein_id: 'ENSP00000419988', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000478531', hgvsp: 'ENSP00000420412.1:p.Gln291LeufsTer11', hgvsc: 'ENST00000478531.1:c.870_871dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000420412', protein_start: 291, protein_end: 291, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000484087', hgvsp: 'ENSP00000419481.1:p.Gln166LeufsTer11', hgvsc: 'ENST00000484087.1:c.495_496dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000419481', protein_start: 166, protein_end: 166, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000487825', hgvsp: 'ENSP00000418212.1:p.Gln167LeufsTer11', hgvsc: 'ENST00000487825.1:c.498_499dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000418212', protein_start: 167, protein_end: 167, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000491747', hgvsp: 'ENSP00000420705.2:p.Gln292LeufsTer11', hgvsc: 'ENST00000491747.2:c.873_874dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000420705', protein_start: 292, protein_end: 292, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, refseq_transcript_ids: ['NM_007298.3'], consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000492859', variant_allele: 'GA', protein_id: 'ENSP00000420253', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000493795', hgvsp: 'ENSP00000418775.1:p.Gln1348LeufsTer11', hgvsc: 'ENST00000493795.1:c.4041_4042dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000418775', protein_start: 1348, protein_end: 1348, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000493919', hgvsp: 'ENSP00000418819.1:p.Gln245LeufsTer11', hgvsc: 'ENST00000493919.1:c.732_733dup', variant_allele: 'GA', codons: 'cag/cTCag', protein_id: 'ENSP00000418819', protein_start: 245, protein_end: 245, gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', amino_acids: 'Q/LX', hgnc_id: 1100, consequence_terms: [ 'frameshift_variant', 'splice_region_variant', ], }, { transcript_id: 'ENST00000494123', variant_allele: 'GA', protein_id: 'ENSP00000419103', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000497488', variant_allele: 'GA', protein_id: 'ENSP00000418986', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000586385', hgvsc: 'ENST00000586385.1:c.5-26996_5-26995dup', variant_allele: 'GA', protein_id: 'ENSP00000465818', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['intron_variant'], }, { transcript_id: 'ENST00000591534', hgvsc: 'ENST00000591534.1:c.-43-16426_-43-16425dup', variant_allele: 'GA', protein_id: 'ENSP00000467329', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['intron_variant'], }, { transcript_id: 'ENST00000591849', hgvsc: 'ENST00000591849.1:c.-99+34324_-99+34325dup', variant_allele: 'GA', protein_id: 'ENSP00000465347', gene_symbol: 'BRCA1', gene_id: 'ENSG00000012048', hgnc_id: 1100, consequence_terms: ['intron_variant'], }, ], annotation_summary: { variant: '17:g.41242962_41242963insGA', genomicLocation: { chromosome: '17', start: 41242962, end: 41242963, referenceAllele: '-', variantAllele: 'GA', }, strandSign: '+', variantType: 'INS', assemblyName: 'GRCh37', canonicalTranscriptId: 'ENST00000357654', transcriptConsequences: [ { transcriptId: 'ENST00000357654', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1395Lfs*11', hgvsp: 'p.Gln1395LeufsTer11', hgvsc: 'ENST00000357654.3:c.4182_4183dup', proteinPosition: { start: 1395, end: 1395, }, refSeq: 'NM_007294.3', variantClassification: 'Frame_Shift_Ins', }, ], transcriptConsequenceSummaries: [ { transcriptId: 'ENST00000309486', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1099Lfs*11', hgvsp: 'p.Gln1099LeufsTer11', hgvsc: 'ENST00000309486.4:c.3294_3295dup', proteinPosition: { start: 1099, end: 1099, }, refSeq: 'NM_007297.3', variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000346315', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1395Lfs*11', hgvsp: 'p.Gln1395LeufsTer11', hgvsc: 'ENST00000346315.3:c.4182_4183dup', proteinPosition: { start: 1395, end: 1395, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000351666', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q212Lfs*11', hgvsp: 'p.Gln212LeufsTer11', hgvsc: 'ENST00000351666.3:c.633_634dup', proteinPosition: { start: 212, end: 212, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000352993', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q253Lfs*11', hgvsp: 'p.Gln253LeufsTer11', hgvsc: 'ENST00000352993.3:c.756_757dup', proteinPosition: { start: 253, end: 253, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000354071', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1395Lfs*11', hgvsp: 'p.Gln1395LeufsTer11', hgvsc: 'ENST00000354071.3:c.4182_4183dup', proteinPosition: { start: 1395, end: 1395, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000357654', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1395Lfs*11', hgvsp: 'p.Gln1395LeufsTer11', hgvsc: 'ENST00000357654.3:c.4182_4183dup', proteinPosition: { start: 1395, end: 1395, }, refSeq: 'NM_007294.3', variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000412061', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000461221', entrezGeneId: '672', consequenceTerms: 'splice_region_variant,3_prime_UTR_variant,NMD_transcript_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.X1322_splice', hgvsc: 'ENST00000461221.1:c.*3965_*3966dup', proteinPosition: { start: 1322, end: 1322, }, variantClassification: 'Splice_Region', }, { transcriptId: 'ENST00000461574', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q160Lfs*11', hgvsp: 'p.Gln160LeufsTer11', hgvsc: 'ENST00000461574.1:c.476_477dup', proteinPosition: { start: 160, end: 160, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000467274', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000468300', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q292Lfs*11', hgvsp: 'p.Gln292LeufsTer11', hgvsc: 'ENST00000468300.1:c.873_874dup', proteinPosition: { start: 292, end: 292, }, refSeq: 'NM_007299.3', variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000470026', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000471181', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1395Lfs*11', hgvsp: 'p.Gln1395LeufsTer11', hgvsc: 'ENST00000471181.2:c.4182_4183dup', proteinPosition: { start: 1395, end: 1395, }, refSeq: 'NM_007300.3', variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000473961', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000476777', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000477152', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000478531', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q291Lfs*11', hgvsp: 'p.Gln291LeufsTer11', hgvsc: 'ENST00000478531.1:c.870_871dup', proteinPosition: { start: 291, end: 291, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000484087', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q166Lfs*11', hgvsp: 'p.Gln166LeufsTer11', hgvsc: 'ENST00000484087.1:c.495_496dup', proteinPosition: { start: 166, end: 166, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000487825', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q167Lfs*11', hgvsp: 'p.Gln167LeufsTer11', hgvsc: 'ENST00000487825.1:c.498_499dup', proteinPosition: { start: 167, end: 167, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000491747', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q292Lfs*11', hgvsp: 'p.Gln292LeufsTer11', hgvsc: 'ENST00000491747.2:c.873_874dup', proteinPosition: { start: 292, end: 292, }, refSeq: 'NM_007298.3', variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000492859', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000493795', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1348Lfs*11', hgvsp: 'p.Gln1348LeufsTer11', hgvsc: 'ENST00000493795.1:c.4041_4042dup', proteinPosition: { start: 1348, end: 1348, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000493919', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q245Lfs*11', hgvsp: 'p.Gln245LeufsTer11', hgvsc: 'ENST00000493919.1:c.732_733dup', proteinPosition: { start: 245, end: 245, }, variantClassification: 'Frame_Shift_Ins', }, { transcriptId: 'ENST00000494123', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000497488', entrezGeneId: '672', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'BRCA1', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000586385', entrezGeneId: '672', consequenceTerms: 'intron_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: '*2*', hgvsc: 'ENST00000586385.1:c.5-26996_5-26995dup', variantClassification: 'Intron', }, { transcriptId: 'ENST00000591534', entrezGeneId: '672', consequenceTerms: 'intron_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: '*15*', hgvsc: 'ENST00000591534.1:c.-43-16426_-43-16425dup', variantClassification: 'Intron', }, { transcriptId: 'ENST00000591849', entrezGeneId: '672', consequenceTerms: 'intron_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: '*33*', hgvsc: 'ENST00000591849.1:c.-99+34324_-99+34325dup', variantClassification: 'Intron', }, ], transcriptConsequenceSummary: { transcriptId: 'ENST00000357654', codonChange: 'cag/cTCag', entrezGeneId: '672', consequenceTerms: 'frameshift_variant,splice_region_variant', hugoGeneSymbol: 'BRCA1', hgvspShort: 'p.Q1395Lfs*11', hgvsp: 'p.Gln1395LeufsTer11', hgvsc: 'ENST00000357654.3:c.4182_4183dup', proteinPosition: { start: 1395, end: 1395, }, refSeq: 'NM_007294.3', variantClassification: 'Frame_Shift_Ins', }, }, }, { variant: '13:g.32912813G>T', originalVariantQuery: '13,32912813,32912813,G,T', colocatedVariants: [ { dbSnpId: 'COSM946800', }, { dbSnpId: 'COSM946801', }, ], id: '13:g.32912813G>T', assembly_name: 'GRCh37', seq_region_name: '13', start: 32912813, end: 32912813, allele_string: 'G/T', strand: 1, most_severe_consequence: 'stop_gained', transcript_consequences: [ { transcript_id: 'ENST00000380152', hgvsp: 'ENSP00000369497.3:p.Glu1441Ter', hgvsc: 'ENST00000380152.3:c.4321G>T', variant_allele: 'T', codons: 'Gag/Tag', protein_id: 'ENSP00000369497', protein_start: 1441, protein_end: 1441, gene_symbol: 'BRCA2', gene_id: 'ENSG00000139618', amino_acids: 'E/*', hgnc_id: 1101, canonical: '1', consequence_terms: ['stop_gained'], }, { transcript_id: 'ENST00000544455', hgvsp: 'ENSP00000439902.1:p.Glu1441Ter', hgvsc: 'ENST00000544455.1:c.4321G>T', variant_allele: 'T', codons: 'Gag/Tag', protein_id: 'ENSP00000439902', protein_start: 1441, protein_end: 1441, gene_symbol: 'BRCA2', gene_id: 'ENSG00000139618', amino_acids: 'E/*', hgnc_id: 1101, refseq_transcript_ids: ['NM_000059.3'], consequence_terms: ['stop_gained'], }, ], annotation_summary: { variant: '13:g.32912813G>T', genomicLocation: { chromosome: '13', start: 32912813, end: 32912813, referenceAllele: 'G', variantAllele: 'T', }, strandSign: '+', variantType: 'SNP', assemblyName: 'GRCh37', canonicalTranscriptId: 'ENST00000380152', transcriptConsequences: [ { transcriptId: 'ENST00000380152', codonChange: 'Gag/Tag', entrezGeneId: '675', consequenceTerms: 'stop_gained', hugoGeneSymbol: 'BRCA2', hgvspShort: 'p.E1441*', hgvsp: 'p.Glu1441Ter', hgvsc: 'ENST00000380152.3:c.4321G>T', proteinPosition: { start: 1441, end: 1441, }, variantClassification: 'Nonsense_Mutation', }, ], transcriptConsequenceSummaries: [ { transcriptId: 'ENST00000380152', codonChange: 'Gag/Tag', entrezGeneId: '675', consequenceTerms: 'stop_gained', hugoGeneSymbol: 'BRCA2', hgvspShort: 'p.E1441*', hgvsp: 'p.Glu1441Ter', hgvsc: 'ENST00000380152.3:c.4321G>T', proteinPosition: { start: 1441, end: 1441, }, variantClassification: 'Nonsense_Mutation', }, { transcriptId: 'ENST00000544455', codonChange: 'Gag/Tag', entrezGeneId: '675', consequenceTerms: 'stop_gained', hugoGeneSymbol: 'BRCA2', hgvspShort: 'p.E1441*', hgvsp: 'p.Glu1441Ter', hgvsc: 'ENST00000544455.1:c.4321G>T', proteinPosition: { start: 1441, end: 1441, }, refSeq: 'NM_000059.3', variantClassification: 'Nonsense_Mutation', }, ], transcriptConsequenceSummary: { transcriptId: 'ENST00000380152', codonChange: 'Gag/Tag', entrezGeneId: '675', consequenceTerms: 'stop_gained', hugoGeneSymbol: 'BRCA2', hgvspShort: 'p.E1441*', hgvsp: 'p.Glu1441Ter', hgvsc: 'ENST00000380152.3:c.4321G>T', proteinPosition: { start: 1441, end: 1441, }, variantClassification: 'Nonsense_Mutation', }, }, }, { variant: '12:g.133214671G>C', originalVariantQuery: '12,133214671,133214671,G,C', colocatedVariants: [ { dbSnpId: 'COSM78324', }, ], id: '12:g.133214671G>C', assembly_name: 'GRCh37', seq_region_name: '12', start: 133214671, end: 133214671, allele_string: 'G/C', strand: 1, most_severe_consequence: 'missense_variant', transcript_consequences: [ { transcript_id: 'ENST00000320574', hgvsp: 'ENSP00000322570.5:p.Asn1869Lys', hgvsc: 'ENST00000320574.5:c.5607C>G', variant_allele: 'C', codons: 'aaC/aaG', protein_id: 'ENSP00000322570', protein_start: 1869, protein_end: 1869, gene_symbol: 'POLE', gene_id: 'ENSG00000177084', amino_acids: 'N/K', hgnc_id: 9177, canonical: '1', polyphen_score: 0.716, polyphen_prediction: 'possibly_damaging', sift_score: 0, sift_prediction: 'deleterious', refseq_transcript_ids: ['NM_006231.2'], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000416953', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['upstream_gene_variant'], }, { transcript_id: 'ENST00000434528', hgvsc: 'ENST00000434528.3:n.590C>G', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['non_coding_transcript_exon_variant'], }, { transcript_id: 'ENST00000441786', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['upstream_gene_variant'], }, { transcript_id: 'ENST00000535270', hgvsp: 'ENSP00000445753.1:p.Asn1842Lys', hgvsc: 'ENST00000535270.1:c.5526C>G', variant_allele: 'C', codons: 'aaC/aaG', protein_id: 'ENSP00000445753', protein_start: 1842, protein_end: 1842, gene_symbol: 'POLE', gene_id: 'ENSG00000177084', amino_acids: 'N/K', hgnc_id: 9177, polyphen_score: 0.408, polyphen_prediction: 'benign', sift_score: 0, sift_prediction: 'deleterious', consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000537064', hgvsc: 'ENST00000537064.1:c.*5358C>G', variant_allele: 'C', protein_id: 'ENSP00000442578', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: [ '3_prime_UTR_variant', 'NMD_transcript_variant', ], }, { transcript_id: 'ENST00000541213', hgvsc: 'ENST00000541213.1:n.1085C>G', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['non_coding_transcript_exon_variant'], }, { transcript_id: 'ENST00000542362', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000544414', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['upstream_gene_variant'], }, { transcript_id: 'ENST00000544692', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['upstream_gene_variant'], }, { transcript_id: 'ENST00000544870', variant_allele: 'C', gene_symbol: 'POLE', gene_id: 'ENSG00000177084', hgnc_id: 9177, consequence_terms: ['upstream_gene_variant'], }, ], annotation_summary: { variant: '12:g.133214671G>C', genomicLocation: { chromosome: '12', start: 133214671, end: 133214671, referenceAllele: 'G', variantAllele: 'C', }, strandSign: '+', variantType: 'SNP', assemblyName: 'GRCh37', canonicalTranscriptId: 'ENST00000320574', transcriptConsequences: [ { transcriptId: 'ENST00000320574', codonChange: 'aaC/aaG', entrezGeneId: '5426', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'POLE', hgvspShort: 'p.N1869K', hgvsp: 'p.Asn1869Lys', hgvsc: 'ENST00000320574.5:c.5607C>G', proteinPosition: { start: 1869, end: 1869, }, refSeq: 'NM_006231.2', variantClassification: 'Missense_Mutation', }, ], transcriptConsequenceSummaries: [ { transcriptId: 'ENST00000320574', codonChange: 'aaC/aaG', entrezGeneId: '5426', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'POLE', hgvspShort: 'p.N1869K', hgvsp: 'p.Asn1869Lys', hgvsc: 'ENST00000320574.5:c.5607C>G', proteinPosition: { start: 1869, end: 1869, }, refSeq: 'NM_006231.2', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000416953', entrezGeneId: '5426', consequenceTerms: 'upstream_gene_variant', hugoGeneSymbol: 'POLE', variantClassification: "5'Flank", }, { transcriptId: 'ENST00000434528', entrezGeneId: '5426', consequenceTerms: 'non_coding_transcript_exon_variant', hugoGeneSymbol: 'POLE', hgvspShort: '*197*', hgvsc: 'ENST00000434528.3:n.590C>G', variantClassification: 'RNA', }, { transcriptId: 'ENST00000441786', entrezGeneId: '5426', consequenceTerms: 'upstream_gene_variant', hugoGeneSymbol: 'POLE', variantClassification: "5'Flank", }, { transcriptId: 'ENST00000535270', codonChange: 'aaC/aaG', entrezGeneId: '5426', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'POLE', hgvspShort: 'p.N1842K', hgvsp: 'p.Asn1842Lys', hgvsc: 'ENST00000535270.1:c.5526C>G', proteinPosition: { start: 1842, end: 1842, }, variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000537064', entrezGeneId: '5426', consequenceTerms: '3_prime_UTR_variant,NMD_transcript_variant', hugoGeneSymbol: 'POLE', hgvspShort: '*1786*', hgvsc: 'ENST00000537064.1:c.*5358C>G', variantClassification: "3'UTR", }, { transcriptId: 'ENST00000541213', entrezGeneId: '5426', consequenceTerms: 'non_coding_transcript_exon_variant', hugoGeneSymbol: 'POLE', hgvspShort: '*362*', hgvsc: 'ENST00000541213.1:n.1085C>G', variantClassification: 'RNA', }, { transcriptId: 'ENST00000542362', entrezGeneId: '5426', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'POLE', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000544414', entrezGeneId: '5426', consequenceTerms: 'upstream_gene_variant', hugoGeneSymbol: 'POLE', variantClassification: "5'Flank", }, { transcriptId: 'ENST00000544692', entrezGeneId: '5426', consequenceTerms: 'upstream_gene_variant', hugoGeneSymbol: 'POLE', variantClassification: "5'Flank", }, { transcriptId: 'ENST00000544870', entrezGeneId: '5426', consequenceTerms: 'upstream_gene_variant', hugoGeneSymbol: 'POLE', variantClassification: "5'Flank", }, ], transcriptConsequenceSummary: { transcriptId: 'ENST00000320574', codonChange: 'aaC/aaG', entrezGeneId: '5426', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'POLE', hgvspShort: 'p.N1869K', hgvsp: 'p.Asn1869Lys', hgvsc: 'ENST00000320574.5:c.5607C>G', proteinPosition: { start: 1869, end: 1869, }, refSeq: 'NM_006231.2', variantClassification: 'Missense_Mutation', }, }, }, { variant: '17:g.7577539G>A', originalVariantQuery: '17,7577539,7577539,G,A', colocatedVariants: [ { dbSnpId: 'CM010465', }, { dbSnpId: 'CM900211', }, { dbSnpId: 'COSM10656', }, { dbSnpId: 'COSM11564', }, { dbSnpId: 'COSM1189381', }, { dbSnpId: 'COSM1189382', }, { dbSnpId: 'COSM1189383', }, { dbSnpId: 'COSM120005', }, { dbSnpId: 'COSM120006', }, { dbSnpId: 'COSM120007', }, { dbSnpId: 'COSM1640831', }, { dbSnpId: 'COSM2744594', }, { dbSnpId: 'COSM3388183', }, { dbSnpId: 'COSM4271789', }, { dbSnpId: 'COSM44920', }, { dbSnpId: 'COSM45116', }, { dbSnpId: 'rs121912651', }, { dbSnpId: 'TP53_g.13379C>T', }, ], id: '17:g.7577539G>A', assembly_name: 'GRCh37', seq_region_name: '17', start: 7577539, end: 7577539, allele_string: 'G/A', strand: 1, most_severe_consequence: 'missense_variant', transcript_consequences: [ { transcript_id: 'ENST00000269305', hgvsp: 'ENSP00000269305.4:p.Arg248Trp', hgvsc: 'ENST00000269305.4:c.742C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000269305', protein_start: 248, protein_end: 248, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, canonical: '1', polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', refseq_transcript_ids: [ 'NM_001126112.2', 'NM_001276761.1', 'NM_001276760.1', 'NM_000546.5', 'NM_001126118.1', ], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000359597', hgvsp: 'ENSP00000352610.4:p.Arg248Trp', hgvsc: 'ENST00000359597.4:c.742C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000352610', protein_start: 248, protein_end: 248, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000413465', hgvsp: 'ENSP00000410739.2:p.Arg248Trp', hgvsc: 'ENST00000413465.2:c.742C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000410739', protein_start: 248, protein_end: 248, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000420246', hgvsp: 'ENSP00000391127.2:p.Arg248Trp', hgvsc: 'ENST00000420246.2:c.742C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000391127', protein_start: 248, protein_end: 248, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', refseq_transcript_ids: ['NM_001126114.2', 'NM_001276696.1'], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000445888', hgvsp: 'ENSP00000391478.2:p.Arg248Trp', hgvsc: 'ENST00000445888.2:c.742C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000391478', protein_start: 248, protein_end: 248, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000455263', hgvsp: 'ENSP00000398846.2:p.Arg248Trp', hgvsc: 'ENST00000455263.2:c.742C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000398846', protein_start: 248, protein_end: 248, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', refseq_transcript_ids: ['NM_001276695.1', 'NM_001126113.2'], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000503591', variant_allele: 'A', protein_id: 'ENSP00000426252', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000504290', hgvsc: 'ENST00000504290.1:n.624C>T', variant_allele: 'A', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: [ 'non_coding_transcript_exon_variant', 'non_coding_transcript_variant', ], }, { transcript_id: 'ENST00000504937', hgvsc: 'ENST00000504937.1:n.624C>T', variant_allele: 'A', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: [ 'non_coding_transcript_exon_variant', 'non_coding_transcript_variant', ], }, { transcript_id: 'ENST00000505014', variant_allele: 'A', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000508793', variant_allele: 'A', protein_id: 'ENSP00000424104', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000509690', hgvsp: 'ENSP00000425104.1:p.Arg116Trp', hgvsc: 'ENST00000509690.1:c.346C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000425104', protein_start: 116, protein_end: 116, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000510385', hgvsc: 'ENST00000510385.1:n.624C>T', variant_allele: 'A', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: [ 'non_coding_transcript_exon_variant', 'non_coding_transcript_variant', ], }, { transcript_id: 'ENST00000514944', hgvsp: 'ENSP00000423862.1:p.Arg155Trp', hgvsc: 'ENST00000514944.1:c.463C>T', variant_allele: 'A', codons: 'Cgg/Tgg', protein_id: 'ENSP00000423862', protein_start: 155, protein_end: 155, gene_symbol: 'TP53', gene_id: 'ENSG00000141510', amino_acids: 'R/W', hgnc_id: 11998, polyphen_score: 1, polyphen_prediction: 'probably_damaging', sift_score: 0, sift_prediction: 'deleterious', consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000574684', variant_allele: 'A', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: ['downstream_gene_variant'], }, { transcript_id: 'ENST00000576024', variant_allele: 'A', protein_id: 'ENSP00000458393', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: ['upstream_gene_variant'], }, { transcript_id: 'ENST00000604348', variant_allele: 'A', protein_id: 'ENSP00000473895', gene_symbol: 'TP53', gene_id: 'ENSG00000141510', hgnc_id: 11998, consequence_terms: ['downstream_gene_variant'], }, ], annotation_summary: { variant: '17:g.7577539G>A', genomicLocation: { chromosome: '17', start: 7577539, end: 7577539, referenceAllele: 'G', variantAllele: 'A', }, strandSign: '+', variantType: 'SNP', assemblyName: 'GRCh37', canonicalTranscriptId: 'ENST00000269305', transcriptConsequences: [ { transcriptId: 'ENST00000269305', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000269305.4:c.742C>T', proteinPosition: { start: 248, end: 248, }, refSeq: 'NM_001126112.2', variantClassification: 'Missense_Mutation', }, ], transcriptConsequenceSummaries: [ { transcriptId: 'ENST00000269305', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000269305.4:c.742C>T', proteinPosition: { start: 248, end: 248, }, refSeq: 'NM_001126112.2', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000359597', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000359597.4:c.742C>T', proteinPosition: { start: 248, end: 248, }, variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000413465', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000413465.2:c.742C>T', proteinPosition: { start: 248, end: 248, }, variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000420246', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000420246.2:c.742C>T', proteinPosition: { start: 248, end: 248, }, refSeq: 'NM_001126114.2', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000445888', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000445888.2:c.742C>T', proteinPosition: { start: 248, end: 248, }, variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000455263', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000455263.2:c.742C>T', proteinPosition: { start: 248, end: 248, }, refSeq: 'NM_001276695.1', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000503591', entrezGeneId: '7157', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'TP53', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000504290', entrezGeneId: '7157', consequenceTerms: 'non_coding_transcript_exon_variant,non_coding_transcript_variant', hugoGeneSymbol: 'TP53', hgvspShort: '*208*', hgvsc: 'ENST00000504290.1:n.624C>T', variantClassification: 'RNA', }, { transcriptId: 'ENST00000504937', entrezGeneId: '7157', consequenceTerms: 'non_coding_transcript_exon_variant,non_coding_transcript_variant', hugoGeneSymbol: 'TP53', hgvspShort: '*208*', hgvsc: 'ENST00000504937.1:n.624C>T', variantClassification: 'RNA', }, { transcriptId: 'ENST00000505014', entrezGeneId: '7157', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'TP53', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000508793', entrezGeneId: '7157', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'TP53', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000509690', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R116W', hgvsp: 'p.Arg116Trp', hgvsc: 'ENST00000509690.1:c.346C>T', proteinPosition: { start: 116, end: 116, }, variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000510385', entrezGeneId: '7157', consequenceTerms: 'non_coding_transcript_exon_variant,non_coding_transcript_variant', hugoGeneSymbol: 'TP53', hgvspShort: '*208*', hgvsc: 'ENST00000510385.1:n.624C>T', variantClassification: 'RNA', }, { transcriptId: 'ENST00000514944', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R155W', hgvsp: 'p.Arg155Trp', hgvsc: 'ENST00000514944.1:c.463C>T', proteinPosition: { start: 155, end: 155, }, variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000574684', entrezGeneId: '7157', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'TP53', variantClassification: "3'Flank", }, { transcriptId: 'ENST00000576024', entrezGeneId: '7157', consequenceTerms: 'upstream_gene_variant', hugoGeneSymbol: 'TP53', variantClassification: "5'Flank", }, { transcriptId: 'ENST00000604348', entrezGeneId: '7157', consequenceTerms: 'downstream_gene_variant', hugoGeneSymbol: 'TP53', variantClassification: "3'Flank", }, ], transcriptConsequenceSummary: { transcriptId: 'ENST00000269305', codonChange: 'Cgg/Tgg', entrezGeneId: '7157', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'TP53', hgvspShort: 'p.R248W', hgvsp: 'p.Arg248Trp', hgvsc: 'ENST00000269305.4:c.742C>T', proteinPosition: { start: 248, end: 248, }, refSeq: 'NM_001126112.2', variantClassification: 'Missense_Mutation', }, }, }, { variant: '10:g.89692905G>A', originalVariantQuery: '10,89692905,89692905,G,A', colocatedVariants: [ { dbSnpId: 'CM981670', }, { dbSnpId: 'CM991081', }, { dbSnpId: 'COSM5033', }, { dbSnpId: 'COSM5216', }, { dbSnpId: 'COSM5277', }, { dbSnpId: 'COSM5817', }, { dbSnpId: 'rs121909229', }, ], id: '10:g.89692905G>A', assembly_name: 'GRCh37', seq_region_name: '10', start: 89692905, end: 89692905, allele_string: 'G/A', strand: 1, most_severe_consequence: 'missense_variant', transcript_consequences: [ { transcript_id: 'ENST00000371953', hgvsp: 'ENSP00000361021.3:p.Arg130Gln', hgvsc: 'ENST00000371953.3:c.389G>A', variant_allele: 'A', codons: 'cGa/cAa', protein_id: 'ENSP00000361021', protein_start: 130, protein_end: 130, gene_symbol: 'PTEN', gene_id: 'ENSG00000171862', amino_acids: 'R/Q', hgnc_id: 9588, canonical: '1', polyphen_score: 0.989, polyphen_prediction: 'probably_damaging', sift_score: 0.02, sift_prediction: 'deleterious', refseq_transcript_ids: ['NM_000314.4'], consequence_terms: ['missense_variant'], }, { transcript_id: 'ENST00000498703', hgvsc: 'ENST00000498703.1:n.215G>A', variant_allele: 'A', gene_symbol: 'PTEN', gene_id: 'ENSG00000171862', hgnc_id: 9588, consequence_terms: [ 'non_coding_transcript_exon_variant', 'non_coding_transcript_variant', ], }, ], annotation_summary: { variant: '10:g.89692905G>A', genomicLocation: { chromosome: '10', start: 89692905, end: 89692905, referenceAllele: 'G', variantAllele: 'A', }, strandSign: '+', variantType: 'SNP', assemblyName: 'GRCh37', canonicalTranscriptId: 'ENST00000371953', transcriptConsequences: [ { transcriptId: 'ENST00000371953', codonChange: 'cGa/cAa', entrezGeneId: '5728', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'PTEN', hgvspShort: 'p.R130Q', hgvsp: 'p.Arg130Gln', hgvsc: 'ENST00000371953.3:c.389G>A', proteinPosition: { start: 130, end: 130, }, refSeq: 'NM_000314.4', variantClassification: 'Missense_Mutation', }, ], transcriptConsequenceSummaries: [ { transcriptId: 'ENST00000371953', codonChange: 'cGa/cAa', entrezGeneId: '5728', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'PTEN', hgvspShort: 'p.R130Q', hgvsp: 'p.Arg130Gln', hgvsc: 'ENST00000371953.3:c.389G>A', proteinPosition: { start: 130, end: 130, }, refSeq: 'NM_000314.4', variantClassification: 'Missense_Mutation', }, { transcriptId: 'ENST00000498703', entrezGeneId: '5728', consequenceTerms: 'non_coding_transcript_exon_variant,non_coding_transcript_variant', hugoGeneSymbol: 'PTEN', hgvspShort: '*72*', hgvsc: 'ENST00000498703.1:n.215G>A', variantClassification: 'RNA', }, ], transcriptConsequenceSummary: { transcriptId: 'ENST00000371953', codonChange: 'cGa/cAa', entrezGeneId: '5728', consequenceTerms: 'missense_variant', hugoGeneSymbol: 'PTEN', hgvspShort: 'p.R130Q', hgvsp: 'p.Arg130Gln', hgvsc: 'ENST00000371953.3:c.389G>A', proteinPosition: { start: 130, end: 130, }, refSeq: 'NM_000314.4', variantClassification: 'Missense_Mutation', }, }, }, ]; let mutationsWithNoGenomicLocation: Partial[]; let mutationsWithGenomicLocation: Partial[]; beforeAll(() => { mutationsWithNoGenomicLocation = [ { gene: { hugoGeneSymbol: 'AR', }, proteinChange: 'L729I', mutationType: '', variantType: '', }, { gene: { hugoGeneSymbol: 'AR', }, proteinChange: 'K222N', mutationType: '', variantType: '', }, { gene: { hugoGeneSymbol: 'BRCA1', }, proteinChange: 'Q1395fs', mutationType: '', variantType: '', }, ]; mutationsWithGenomicLocation = [ { chromosome: 'X', startPosition: 66937331, endPosition: 66937331, referenceAllele: 'T', variantAllele: 'A', }, { chromosome: '17', startPosition: 41242962, endPosition: 41242963, referenceAllele: '-', variantAllele: 'GA', }, { chromosome: '13', startPosition: 32912813, endPosition: 32912813, referenceAllele: 'G', variantAllele: 'T', }, { chromosome: '12', startPosition: 133214671, endPosition: 133214671, referenceAllele: 'G', variantAllele: 'C', }, { chromosome: '17', startPosition: 7577539, endPosition: 7577539, referenceAllele: 'G', variantAllele: 'A', }, { chromosome: '10', startPosition: 89692905, endPosition: 89692905, referenceAllele: 'G', variantAllele: 'A', }, ]; }); describe('annotateMutation', () => { it('should handle failed annotations properly', () => { const mutation: Partial = { chromosome: '6', startPosition: 29910348, endPosition: 29910352, referenceAllele: 'CCGAA', variantAllele: 'C', }; const indexedVariantAnnotations = { '6,29910348,29910352,CCGAA,C': { originalVariantQuery: '6,29910348,29910352,CCGAA,C', successfully_annotated: false, variant: '6:g.29910349_29910352del', } as VariantAnnotation, }; const annotatedMutation = annotateMutation( mutation, indexedVariantAnnotations ); assert.equal( annotatedMutation.proteinChange, '', 'protein change value should be empty due to annotation failure' ); }); }); describe('annotateMutations', () => { it("won't annotate mutation data if there are no mutations", () => { const indexedVariantAnnotations = indexAnnotationsByGenomicLocation( [] ); const data = annotateMutations([], indexedVariantAnnotations); assert.equal( data.length, 0, 'annotated mutation data should be empty' ); }); it("won't annotate mutation data if there are no mutations with genomic coordinate information", () => { const indexedVariantAnnotations = indexAnnotationsByGenomicLocation( [] ); const data = annotateMutations( _.cloneDeep(mutationsWithNoGenomicLocation), indexedVariantAnnotations ); assert.deepEqual( data, mutationsWithNoGenomicLocation, 'annotated mutation data should be identical to the initial input' ); }); it('annotates mutation data when the genomic coordinate information is present', () => { const indexedVariantAnnotations = indexAnnotationsByGenomicLocation( variantAnnotations as any[] ); const data = annotateMutations( mutationsWithGenomicLocation, indexedVariantAnnotations ); assert.notDeepEqual( data, mutationsWithGenomicLocation, 'annotated mutation data should be different than the initial input' ); assert.equal(data[0].gene!.hugoGeneSymbol, 'AR'); assert.isTrue(data[0].proteinChange!.includes('L729I')); assert.isTrue(data[0].mutationType!.includes('Missense')); assert.equal(data[1].gene!.hugoGeneSymbol, 'BRCA1'); assert.isTrue(data[1].proteinChange!.includes('Q1395Lfs*11')); assert.isTrue(data[1].mutationType!.includes('Frame_Shift_Ins')); assert.equal(data[2].gene!.hugoGeneSymbol, 'BRCA2'); assert.isTrue(data[2].proteinChange!.includes('E1441*')); assert.isTrue(data[2].mutationType!.includes('Nonsense')); assert.equal(data[3].gene!.hugoGeneSymbol, 'POLE'); assert.isTrue(data[3].proteinChange!.includes('N1869K')); assert.isTrue(data[3].mutationType!.includes('Missense')); assert.equal(data[4].gene!.hugoGeneSymbol, 'TP53'); assert.isTrue(data[4].proteinChange!.includes('R248W')); assert.isTrue(data[4].mutationType!.includes('Missense')); assert.equal(data[5].gene!.hugoGeneSymbol, 'PTEN'); assert.isTrue(data[5].proteinChange!.includes('R130Q')); assert.isTrue(data[5].mutationType!.includes('Missense')); }); }); describe('resolveMissingProteinPositions', () => { it('resolves missing protein positions from protein change value', () => { const mutations: Partial[] = [ { proteinChange: 'L729I', }, { proteinChange: 'K222N', }, { aminoAcidChange: 'Q1395fs', }, { proteinChange: 'INVALID', }, ]; resolveMissingProteinPositions(mutations); assert.equal( mutations[0].proteinPosStart, 729, 'proteinChange = L729I => proteinPosStart = 729' ); assert.equal( mutations[1].proteinPosStart, 222, 'proteinChange = K222N => proteinPosStart = 222' ); assert.equal( mutations[2].proteinPosStart, 1395, 'aminoAcidChange = Q1395fs => proteinPosStart = 1395' ); assert.isUndefined( mutations[3].proteinPosStart, 'invalid proteinChange => proteinPosStart = undefined' ); }); }); });