ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10024G>A (p.Glu3342Lys) (rs28897761)

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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 RCV000220854 SCV000274258 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
GeneDx RCV000445222 SCV000526510 likely benign not specified 2016-12-13 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.
Invitae RCV000463710 SCV000549705 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 3342 of the BRCA2 protein (p.Glu3342Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer and in an independent  family affected with breast and/or ovarian cancer (PMID: 22711857, 27062684). ClinVar contains an entry for this variant (Variation ID: 37718). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000445222 SCV000694487 uncertain significance not specified 2019-07-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10024G>A (p.Glu3342Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250966 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.10024G>A, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Alsop_2012, Azzollini_2016). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reports that this variant was found to co-occur with a pathogenic change but do specify the pathogenic variant (Alsop_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x uncertain significance and 2x benign). Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
Color RCV000220854 SCV000911853 likely benign Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031299 SCV000053904 likely benign Breast-ovarian cancer, familial 2 2009-04-15 no assertion criteria provided clinical testing

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