ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
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 Lines of evidence used in support of classification: 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 RCV000588917 SCV000694637 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2837A>G (p.Asp946Gly) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant, however, no functional studies have been performed to date. This variant is absent from the ExAC database (0/120672 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases have conflicting classifications of uncertain significance (GeneDx in June 2014 and BIC [no date of evaluation provided]) or likely benign (Ambry Genetics in Dec 2015). In addition, the variant of interest has been found to co-occur with two pathogenic BRCA2 mutations (BIC - c.5454_5454delA; p.Ser1818=fs and UMD - c.2701delC; p.Ala902LeufsX2), which suggests a lack of involvement in disease. Taken together, this variant is 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 2018-07-23 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.