ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2791G>T (p.Val931Leu) (rs763639161)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206628 SCV000260043 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-20 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 931 of the BRCA1 protein (p.Val931Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs763639161, ExAC 0.001%). This variant has been reported in an individual affected with hereditary breast and ovarian cancer (PMID: 27376475). ClinVar contains an entry for this variant (Variation ID: 219899). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000255742 SCV000321422 uncertain significance not provided 2018-01-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2791G>T at the cDNA level, p.Val931Leu (V931L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). Using alternate nomenclature, this variant would be defined as BRCA1 2910G>T. This variant was observed in at least one hereditary breast and ovarian cancer patient, however the individual phenotype was not provided (Schenkel 2016). BRCA1 Val931Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Val931Leu is located within the DNA and RAD51 binding domains (Chen 1998, Narod 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Val931Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575467 SCV000668426 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000575467 SCV000904127 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779872 SCV000916745 uncertain significance not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2791G>T (p.Val931Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 121386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2791G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with other pathogenic variant has been reported (MLH1 c.1459C>T, p.Arg487X) in an internam specimen, providing supporting evidence for a benign role. Three 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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