ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8068G>A (p.Val2690Ile) (rs587776471)

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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 RCV000565764 SCV000668805 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000482878 SCV000565780 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8068G>A at the cDNA level, p.Val2690Ile (V2690I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 8296G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val2690Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2690Ile is located within the DNA binding and the nuclear exporting signal (Yang 2002, Jeyasekharan 2013). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Val2690Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000554038 SCV000635633 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-19 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2690 of the BRCA2 protein (p.Val2690Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. 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: 156175). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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. 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.
Sharing Clinical Reports Project (SCRP) RCV000144192 SCV000189265 uncertain significance Breast-ovarian cancer, familial 2 2009-08-06 no assertion criteria provided clinical testing

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