ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.10076A>G (p.Glu3359Gly) (rs80358389)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043708 SCV000071721 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 3359 of the BRCA2 protein (p.Glu3359Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 27062684). This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033) and in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 51038). 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 glycine 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.
Ambry Genetics RCV000222126 SCV000276205 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-15 criteria provided, single submitter clinical testing
Counsyl RCV000112835 SCV000786339 uncertain significance Breast-ovarian cancer, familial 2 2018-04-09 criteria provided, single submitter clinical testing
Color RCV000222126 SCV000911439 likely benign Hereditary cancer-predisposing syndrome 2016-10-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781059 SCV000918850 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.10076A>G (p.Glu3359Gly) results in a non-conservative amino acid change near the C-terminal end of the protein that does not belong to any known functional domain. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was found in 3/276922 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.1e-05 vs 0.00075), allowing no conclusion about variant significance. A publication reports the variant in 1 Hereditary Breast and Ovarian Cancer individual (Azzollini 2016), however this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant have been reported (BRCA1 c.3756_3759delGTCT, p.Ser1253ArgfsX10), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000112835 SCV001139284 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112835 SCV000145747 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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