ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.581G>A (p.Trp194Ter) (rs80358809)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000656583 SCV000885093 pathogenic not provided 2017-12-03 criteria provided, single submitter clinical testing The BRCA2 c.581G>A; p.Trp194Ter variant (rs80358809) introduces an early termination codon and is predicted to result in a truncated protein or mRNA that is subject to nonsense mediated decay. This variant has been reported in the literature in a family affected with breast cancer (Couch 1996). In vitro functional assays show the variant causes exon 7 skipping (Biswas 2011, Di Giacomo 2013), alters BRCA1 nuclear localization and has reduced p53 phosphorylation (Loke 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 51943), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Taken together, the p.Trp194Ter variant is considered pathogenic. REFERENCES Biswas K et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood. 2011 Sep 1;118(9):2430-42. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. Di Giacomo D et al. Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. Hum Mutat. 2013 Nov;34(11):1547-57. Loke J et al. Functional variant analyses (FVAs) predict pathogenicity in the BRCA1 DNA double-strand break repair pathway. Hum Mol Genet. 2015 Jun 1;24(11):3030-7.
Breast Cancer Information Core (BIC) (BRCA2) RCV000077362 SCV000147206 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077362 SCV000327289 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077362 SCV000785775 pathogenic Breast-ovarian cancer, familial 2 2017-11-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656583 SCV000858443 pathogenic not provided 2017-12-06 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077362 SCV000300335 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Integrated Genetics/Laboratory Corporation of America RCV000044763 SCV000916896 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.581G>A (p.Trp194X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.658_659delGT (p.Val220fsX4), c.700delT (p.Ser234fsX7), c.729_732delTGAT (p.Asn243fsX7)). However, functional studies indicated that the variant also affects mRNA splicing, i.e. increasing exon 4-7 and exon 7 skipping compared to WT (Biswas 2011, Di Giacomo 2013) and can generate a protein albeit with decreased ability to rescue the lethality of BRCA2-null embryonic stem cells (Biswas 2011) and with reduced p53 phosphorylation (Loke 2015). The variant was absent in 246192 control chromosomes (gnomAD). c.581G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Couch 1996, Gayther 1997, Chan 2018). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000044763 SCV000072776 pathogenic Hereditary breast and ovarian cancer syndrome 2016-11-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 194 (p.Trp194*) of the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in the literature in patients affected with breast cancer (PMID: 8673091, 26577449). Experimental in vitro assays have shown that this variant results in increased exon 7 skipping (PMID: 21719596, 23983145), altered BRCA1 protein nuclear localization and reduced p53 phosphorylation (PMID: 25652403) For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000656583 SCV000778634 pathogenic not provided 2017-12-07 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077362 SCV000109159 pathogenic Breast-ovarian cancer, familial 2 2010-10-11 no assertion criteria provided clinical testing

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