ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2330A>G (p.Asp777Gly) (rs780489283)

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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 RCV000164609 SCV000215272 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Color RCV000164609 SCV000688750 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000409339 SCV000489712 uncertain significance Breast-ovarian cancer, familial 2 2016-11-11 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481454 SCV000591800 likely benign not specified 2013-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000481454 SCV000567766 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2330A>G at the cDNA level, p.Asp777Gly (D777G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 2558A>G. This variant was observed in a cohort of 1,525 patients that underwent BRCA1/2 analysis (Caux-Moncoutier 2011). BRCA2 Asp777Gly 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 Asp777Gly occurs at a position that is not conserved and is located in the region of interaction with NPM1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asp777Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000196448 SCV000254174 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 777 of the BRCA2 protein (p.Asp777Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs780489283, ExAC <0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 185230). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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