ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2837A>G (p.Asp946Gly) (rs55972907)

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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 RCV000132081 SCV000187145 likely benign Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);in silico models in agreement (benign)
GeneDx RCV000588917 SCV000210294 uncertain significance not provided 2014-06-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2837A>G at the cDNA level, p.Asp946Gly (D946G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp946Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp946Gly occurs at a position that is moderately conserved throughout evolution with Glycine being the naturally occurring amino acid at this position in several species. This variant is located within the region responsible for interaction with NPM1 (UniProt). In addition, multiple in silico models predict that this variant is unlikely to alter protein structure or function. However, a subset of splice predictor models predict the potential creation of a cryptic donor splice site. Based on currently available information, it is unclear whether BRCA2 Asp946Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855581 SCV000694637 uncertain significance not specified 2019-06-06 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2837A>G (p.Asp946Gly) results in a non-conservative amino acid change in 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 4e-06 in 250610 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2837A>G has been reported in the literature in an individual affected with breast cancer, however without strong evidence for causality (Encinas_2018). Co-occurrences with other pathogenic BRCA2 variants have been reported (c.5454delA (p.Cys1820AlafsX20) in an internal sample and in the NHGRI BIC database and c.2701delC (p.Ala902LeufsX2) in the UMD database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as likely benign (1x) or VUS (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl RCV000113103 SCV000786586 uncertain significance Breast-ovarian cancer, familial 2 2018-06-04 criteria provided, single submitter clinical testing
Color RCV000132081 SCV000906894 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113103 SCV000146128 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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