ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2779A>G (p.Met927Val) (rs786201837)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164328 SCV000214959 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164328 SCV000906050 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing
Counsyl RCV000663056 SCV000786108 uncertain significance Breast-ovarian cancer, familial 2 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000426572 SCV000521705 likely benign not specified 2017-11-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000588268 SCV000694625 likely benign not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2779A>G (p.Met927Val) variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome, which are supported by functional studies (Balia_2011 and Spugnesi_2013). Balia_2011 indicates the variant of interest acts comparable to wild type for homologous recombination. This variant is absent in 120756 control chromosomes. Multiple publications have cited the variant in affected individuals including Balia_2011, whom indicates that the variant did not cosegregate with disease in a family. In addition, a clinical diagnostic laboratory classifies the variant as "likely benign," although another classifies the variant as "uncertain significance." Therefore, the variant of interest has been classified as "likely benign," due to the indicated lack of cosegregation and observed comparable wild type HR function.
Invitae RCV000525226 SCV000635245 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 927 of the BRCA2 protein (p.Met927Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (rs786201837, ExAC no frequency). This variant has been reported in a family affected with breast and ovarian cancer, but it did not segregate with disease (PMID: 21671020). ClinVar contains an entry for this variant (Variation ID: 184978). Experimental studies in yeast and human cells have shown that this missense change does not adversely impact homologous recombination (PMID: 21671020, 23328489). In summary, this variant is a rare missense change that does not adversely affect homologous recombination, and has been shown not to segregate with disease in a single family. There is little indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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