ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8293T>G (p.Cys2765Gly) (rs768247528)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165936 SCV000216692 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000239098 SCV000785678 uncertain significance Breast-ovarian cancer, familial 2 2017-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000478794 SCV000568100 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8293T>G at the cDNA level, p.Cys2765Gly (C2765G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8521T>G. This variant was observed in a normal tissue sample from an individual with clear cell renal carcinoma (Lu 2015). BRCA2 Cys2765Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys2765Gly occurs at a position that is conserved across species and is located within the region known for interaction with SHFM1 (Marston 1999). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Cys2765Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000226067 SCV000283338 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 2765 of the BRCA2 protein (p.Cys2765Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is present in population databases (rs768247528, ExAC 0.02%). This variant has been observed in an individual affected with renal clear cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 186355). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Sharing Clinical Reports Project (SCRP) RCV000239098 SCV000297565 uncertain significance Breast-ovarian cancer, familial 2 2013-07-01 no assertion criteria provided clinical testing

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