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example-solid-tumor-deletions.txt
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example-solid-tumor-deletions.txt
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Hugo_Symbol Entrez_Gene_Id Center NCBI_Build Chromosome Start_Position End_Position Strand Consequence Variant_Classification Variant_Type Reference_Allele Tumor_Seq_Allele1 Tumor_Seq_Allele2 dbSNP_RS dbSNP_Val_Status Tumor_Sample_Barcode Matched_Norm_Sample_Barcode Match_Norm_Seq_Allele1 Match_Norm_Seq_Allele2 Tumor_Validation_Allele1 Tumor_Validation_Allele2 Match_Norm_Validation_Allele1 Match_Norm_Validation_Allele2 Verification_Status Validation_Status Mutation_Status Sequencing_Phase Sequence_Source Validation_Method Score BAM_File Sequencer t_ref_count t_alt_count n_ref_count n_alt_count HGVSc HGVSp HGVSp_Short Transcript_ID RefSeq Protein_position Codons Exon_Number COMMENTS AA_MAF AFR_MAF ALLELE_NUM AMR_MAF ASN_MAF Allele Amino_Acid_Change Amino_acids BIOTYPE CANONICAL CCDS CDS_position CLIN_SIG Comments DISTANCE DOMAINS EAS_MAF EA_MAF ENSP EUR_MAF EXON ExAC_AF ExAC_AF_AFR ExAC_AF_AMR ExAC_AF_EAS ExAC_AF_FIN ExAC_AF_NFE ExAC_AF_OTH ExAC_AF_SAS Existing_variation FILTER Feature Feature_type GENE_PHENO GMAF Gene HGNC_ID HGVS_OFFSET HIGH_INF_POS IMPACT INTRON IS_NEW MA:FIS MA:FImpact MA:link.MSA MA:link.PDB MA:link.var MA:protein.change MINIMISED MOTIF_NAME MOTIF_POS MOTIF_SCORE_CHANGE PHENO PICK PUBMED PolyPhen SAS_MAF SIFT SOMATIC SWISSPROT SYMBOL SYMBOL_SOURCE TREMBL TSL Transcript UNIPARC VARIANT_CLASS all_effects amino_acid_change cDNA_Change cDNA_position cdna_change comments n_depth t_depth transcript
CHEK2 11200 MSKCC GRCh37 22 29091227 29091227 + frameshift_variant Frame_Shift_Del DEL A A - rs587780174 P-0044371-T01-IM6 Unknown GERMLINE MSK-IMPACT 334 212 ENST00000328354.6:c.1263del p.Ser422ValfsTer15 p.S422Vfs*15 ENST00000328354 NM_007194.3 421 ctT/ct 12/15 This heterozygous CHEK2 c.1263delT variant is predicted to cause a frameshift, and leads to a premature termination codon 15 amino acids downstream (p.Ser422Valfs*15). This alteration is predicted to lead to a truncated or absent protein, and truncating variants in CHEK2 are known to be pathogenic. This variant has been identified in 0.009% of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org/; dbSNP), and has been reported in individuals affected with breast, prostate, bladder, colon and urethral cancer (PMID: 21244692, 24113346, 24556621, 26534844, 26681312, 27273131, 28779002, 29520813, 29961768). In summary, based on the previous reports of this variant in individuals with CHEK2 associated disease and its truncating effect on the protein, this variant is classified as pathogenic Studies indicate that pathogenic variants in CHEK2 confer an increased risk of developing many types of cancer, including breast, colon, prostate, and other cancers (PMID: 18004398).
RAD51D 5892 MSKCC GRCh37 17 33428375 33428375 + frameshift_variant Frame_Shift_Del DEL G G - rs587780105 P-0030023-T01-IM6 Unknown GERMLINE MSK-IMPACT 26 130 ENST00000335858.7:c.412del p.His138ThrfsTer2 p.H138Tfs*2 ENST00000335858 NM_133629.2 138 Cac/ac 6/7 This heterozygous RAD51D c.748delC variant is predicted to cause a frameshift, and leads to a premature termination codon 2 amino acids downstream (p.His250Thrfs*2). This alteration is predicted to lead to a truncated or absent protein, and truncating variants in RAD51D are known to be pathogenic. This variant has been found in one chromosome in gnomAD, and has been reported in the literature in individuals with breast and ovarian cancers (PMID: 25452441, 26261251, 26681312). In summary, based on the previous reports of this variant in individuals with RAD51D associated cancers and its truncating effect on the protein, this variant meets our criteria to be classified as pathogenic. Pathogenic RAD51D germline variants have been associated with an increased risk of ovarian cancer (PMID: 21822267, 26261251).
RAD51C 5889 MSKCC GRCh37 17 56809909 56809911 + splice_region_variant,intron_variant Splice_Region DEL AGT AGT - rs1313421513 P-0018929-T01-IM6 Unknown GERMLINE MSK-IMPACT 0 0 ENST00000337432.4:c.1026+5_1026+7del p.X342_splice ENST00000337432 NM_058216.2 342 The heterozygous germline RAD51C deletion, c.1026+5_1026+7delGTA, consists of a deletion of three nucleotides at the +5 to +7 positions of intron 8. This variant was reported in three families with early onset breast and/or ovarian cancers (PMID: 26057125, 24139550, and 27616075). This variant is predicted to affect the natural splice donor site by multiple algorithms. Functional analysis indicated this variant results in an out-of-frame exon 8 skipping and is expected to lead to an absent or truncated protein in two independent studies (PMID: 26057125, 24139550). RAD51C mutations have been reported in breast and ovarian cancer families (PMID: 22451500, 20400964) and confer increased risk of ovarian (PMID: 26261251). Based on the currently available information, we consider RAD51C c.1026+5_1026+7delGTA to be a likely pathogenic variant.
BRCA2 675 MSKCC GRCh37 13 32914438 32914438 + frameshift_variant Frame_Shift_Del DEL T T - rs80359550 P-0034227-T01-IM6 Unknown GERMLINE MSK-IMPACT 0 0 ENST00000380152.3:c.5946del p.Ser1982ArgfsTer22 p.S1982Rfs*22 ENST00000380152 1982 agT/ag 11/27 The heterozygous BRCA2 c.5946delT (p.Ser1982Argfs *22) germline variant leads to a premature stop codon at amino acid position 2003 and is expected to result in an absent or disrupted protein product. This mutation confers an increased risk of breast cancer and ovarian cancer in women and of breast cancer in men, and is a founder mutation in the Ashkenazi Jewish population (PubMed 9042909 ). Additionally, BRCA2 mutations may also confer an increased risk of other cancers including pancreatic cancer (PubMed 9140390 ) and prostate cancer (PubMed 11170890 ). Because the mutation is transmitted with a probability of 50% from a carrier parent to child, we also recommend testing for this disease-causing mutation in the relatives of the patient as appropriate. Note: BRCA2 c.5946delT is also known as BRCA2 6174delT.
BRCA1 672 MSKCC GRCh37 17 41251825 41251825 + frameshift_variant Frame_Shift_Del DEL G G - rs80357872 P-0030162-T01-IM6 Unknown GERMLINE MSK-IMPACT 224 201 ENST00000357654.3:c.514del p.Gln172AsnfsTer62 p.Q172Nfs*62 ENST00000357654 NM_007294.3 172 Caa/aa 7/23 This heterozygous BRCA1 c.514delC variant is predicted to cause a frameshift and lead to a premature termination codon 62 amino acids downstream (p.Gln172Asnfs*62). This alteration is predicted to lead to a truncated or absent protein, and truncating variants in BRCA1 are known to be pathogenic. This variant is absent from large population databases (1000 Genomes, ESP, Broad ExAC, gnomAD) and has been reported in individuals with breast, ovarian, and pancreatic cancer (PMID: 10528853, 17221156, 17591842, 18042939, 19818148, 21989927, 25682074, 26219728). In summary, based on the previous reports of this variant in individuals with BRCA1 associated cancers and its truncating effect on the protein, this variant meets our criteria to be classified as pathogenic. Note: This variant may also be referred to as BRCA1 633delC in the literature. Women carrying a pathogenic BRCA1 mutation are at increased risk of developing breast and ovarian cancers. Additionally, BRCA1 pathogenic variants have been associated with an increased risk of other cancers including prostate cancer and pancreatic cancer (PMID: 12237281).
MSH3 4437 MSKCC GRCh37 5 79968628 79968634 + frameshift_variant Frame_Shift_Del DEL TTCCCGG TTCCCGG - rs1475633334 P-0024969-T01-IM6 Unknown GERMLINE MSK-IMPACT 0 0 ENST00000265081.6:c.978_984del p.Phe326LeufsTer3 p.F326Lfs*3 ENST00000265081 NM_002439.4 326 ttTTCCCGG/tt 6/24 This individual was found to be heterozygous (monoallelic mutation carrier) for the MSH3 c.978_984delTTCCCGG variant. This heterozygous MSH3 c.978_984delTTCCCGG variant is predicted to cause a frameshift, and leads to a premature termination codon 3 amino acids downstream (p.Phe326Leufs*3). This variant has been identified in <0.01% of chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has not, to our knowledge, been reported in the literature. Based on the truncating nature of this variant, it is classified as likely pathogenic. Biallelic MSH3 germline mutations are associated with autosomal recessive colorectal adenomatous polyposis (PMID: 27476653). If a monoallelic MSH3 mutation carriers partner is also a monoallelic carrier for a pathogenic MSH3 mutation, there is a 25% risk that each child would have two germline MSH3 pathogenic variants. Such individuals would have an increased risk for colorectal polyposis.
MSH3 4437 MSKCC GRCh37 5 79968628 79968634 + frameshift_variant Frame_Shift_Del DEL TTCCCGG TTCCCGG - rs1475633334 P-0024969-T02-IM6 Unknown GERMLINE MSK-IMPACT 0 0 ENST00000265081.6:c.978_984del p.Phe326LeufsTer3 p.F326Lfs*3 ENST00000265081 NM_002439.4 326 ttTTCCCGG/tt 6/24 This individual was found to be heterozygous (monoallelic mutation carrier) for the MSH3 c.978_984delTTCCCGG variant. This heterozygous MSH3 c.978_984delTTCCCGG variant is predicted to cause a frameshift, and leads to a premature termination codon 3 amino acids downstream (p.Phe326Leufs*3). This variant has been identified in <0.01% of chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has not, to our knowledge, been reported in the literature. Based on the truncating nature of this variant, it is classified as likely pathogenic. Biallelic MSH3 germline mutations are associated with autosomal recessive colorectal adenomatous polyposis (PMID: 27476653). If a monoallelic MSH3 mutation carriers partner is also a monoallelic carrier for a pathogenic MSH3 mutation, there is a 25% risk that each child would have two germline MSH3 pathogenic variants. Such individuals would have an increased risk for colorectal polyposis.
MLH1 4292 MSKCC GRCh37 3 37089123 37089125 + inframe_deletion In_Frame_Del DEL GAA GAA - rs1485223012 P-0062645-T01-IM7 Unknown GERMLINE MSK-IMPACT 0 0 ENST00000231790.2:c.1852_1854del p.Lys618del p.K618del ENST00000231790 NM_000249.3 615 ctGAAg/ctg 16/19 This sequence change deletes 3 nucleotides from exon 16 of the MLH1 gene (c.1852_1854delAAG), and leads to the deletion of 1 amino acid from the MLH1 protein (p.Lys618del). This variant has been identified in 1/113698 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org). It has been reported in the literature in many families with Lynch syndrome (PMID: 10422993, 12891553, 17569143, 21642682, 21681552.) Functional studies have shown that this variant leads to reduced MLH1 expression and abrogated function (PMID: 12891553, 17510385). The International Society for Gastrointestinal Hereditary Tumours (http://insight-group.org/) classifies this variant as pathogenic. In summary, based on the previous reports of this variant in many individuals with MLH1 associated cancers, this variant meets our criteria to be classified as pathogenic. Note: This variant may also be referred to as MLH1 K616del in the literature. Lynch syndrome is an autosomal dominant condition that confers an increased risk for colorectal cancer and endometrial cancers as well as other cancers. There is a 50% chance that each child would inherit this variant from a parent.
WHSC1 0 MSKCC GRCh37 4 1956906 1956918 + frameshift_variant Frame_Shift_Del DEL TCCGCTGCCCCGT TCCGCTGCCCCGT - P-0009561-T02-IM7 Unknown SOMATIC MSK-IMPACT 404 95 356 0 ENST00000382895.3:c.2358_2370del p.Arg787ProfsTer15 p.R787Pfs*15 ENST00000382895 NM_133330.2 786 gTCCGCTGCCCCGTt/gt