ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7828G>A (p.Val2610Met) (rs587780661)

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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 RCV000217800 SCV000276951 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing
Color RCV000217800 SCV000689071 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000589148 SCV000568487 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7828G>A at the cDNA level, p.Val2610Met (V2610M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 8056G>A. This variant was observed in at least one patient with breast cancer and was also identified in an individual undergoing testing for hereditary breast and ovarian cancer (Whiley 2014, Lincoln 2015). An RT-PCR in vitro assay by Whiley et al. (2014) demonstrated no effect on splicing. BRCA2 Val2610Met was not observed in large population cohorts (Lek 2016). This variant is located within the DNA and SHFM1 binding domains (Marston 1999, 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 Val2610Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589148 SCV000695104 uncertain significance not provided 2016-09-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7828G>A (p.Val2610Met) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121188 control chromosomes, and has been reported in patients in the literature without strong evidence for causality. 4/5 splicing tools via Alamut predict the variant does affect splicing. However, RT-PCR analysis indicates the variant to have no effect on splicing (Whiley_2014). From text: Despite predictions of an increased likelihood of creating a de novo donor site by MaxEntScan for BRCA2, c.7828G>A (p.Val2610Met), there was no evidence for the predicted aberration from RT-PCR analysis." Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, this variant is classified as VUS until additional evidence becomes available.
Invitae RCV000122932 SCV000166190 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 2610 of the BRCA2 protein (p.Val2610Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 24489791). ClinVar contains an entry for this variant (Variation ID: 135816). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). An experimental study has shown that this missense change does not affect mRNA splicing (PMID: 24489791). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, 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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