ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2330A>G (p.Asp777Gly) (rs780489283)

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Total submissions: 7
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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 2018-12-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Invitae RCV000196448 SCV000254174 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-27 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, 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.
Counsyl RCV000409339 SCV000489712 uncertain significance Breast-ovarian cancer, familial 2 2016-11-11 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481454 SCV000591800 likely benign not specified 2013-06-05 criteria provided, single submitter clinical testing
Color RCV000164609 SCV000688750 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000481454 SCV001362887 uncertain significance not specified 2020-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2330A>G (p.Asp777Gly) 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 1.2e-05 in 250960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2330A>G has been reported in the literature in at-least one individual affected with Breast Cancer (Caux-Moncoutier_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). 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.

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