ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2959A>G (p.Lys987Glu) (rs878854941)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230349 SCV000289767 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-02-10 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 987 of the BRCA1 protein (p.Lys987Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no 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.
Ambry Genetics RCV000509909 SCV000608222 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-11 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000509909 SCV000905268 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779897 SCV000916794 uncertain significance not specified 2018-08-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2959A>G (p.Lys987Glu) 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 was absent in 245952 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2959A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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