ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1901del (p.Ala634fs)

dbSNP: rs397507614
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000661802 SCV000784121 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577776 SCV000678724 not provided Familial cancer of breast no assertion provided literature only
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355542 SCV001550461 pathogenic not provided no assertion criteria provided clinical testing The BRCA2 p.Ala634ValfsX10 variant was identified in 1 of 978 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Li 2008). The variant was also identified in dbSNP (ID: rs397507614) as “With untested allele”, in ClinVar (classification not provided), ARUP Laboratories (as Definitely pathogenic ), and Zhejiang University (1x as Pathogenic ). The variant was not identified in GeneInsight-COGR, Cosmic, UMD-LSDB, or BIC databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The c.1901del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 634 and leads to a premature stop codon at position 644. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in BRCA associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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