ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8183T>C (p.Val2728Ala) (rs587781719)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129903 SCV000184721 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000663059 SCV000786115 uncertain significance Breast-ovarian cancer, familial 2 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000523831 SCV000617876 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8183T>C at the cDNA level, p.Val2728Ala (V2728A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). Using alternate nomenclature, this variant would be defined as BRCA2 8411T>C. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Val2728Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located at a DSS1 contacting residue in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Val2728Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000463515 SCV000549863 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2728 of the BRCA2 protein (p.Val2728Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141399). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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