ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8125A>G (p.Ser2709Gly) (rs398122596)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198708 SCV000254218 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 2709 of the BRCA2 protein (p.Ser2709Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs398122596, ExAC 0.01%). This variant has been reported in an individual affected with glioblastoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 91501). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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 RCV000235393 SCV000293619 uncertain significance not provided 2018-04-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8125A>G at the cDNA level, p.Ser2709Gly (S2709G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8353A>G. This variant was observed in a normal tissue sample from an individual with glioblastoma (Lu 2015). BRCA2 Ser2709Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA Binding Domain (Yang 2002). 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 BRCA2 Ser2709Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077018 SCV000296513 uncertain significance Breast-ovarian cancer, familial 2 2016-05-17 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768638 SCV000324855 uncertain significance Breast and/or ovarian cancer 2015-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569993 SCV000661204 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000569993 SCV000906506 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779969 SCV000916936 uncertain significance not specified 2018-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8125A>G (p.Ser2709Gly) results in a non-conservative amino acid change located in the BRCA2, OB1 of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.8125A>G has not been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Sharing Clinical Reports Project (SCRP) RCV000077018 SCV000108815 uncertain significance Breast-ovarian cancer, familial 2 2011-07-13 no assertion criteria provided clinical testing

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