ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5131G>A (p.Val1711Ile) (rs587782067)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130552 SCV000185422 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000586102 SCV000694830 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5131G>A (p.Val1711Ile) variant causes a missense change involving a non-conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. Although, a clinical diagnostic laboratory and database cite the variant as "uncertain signficance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000797822 SCV000937404 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1711 of the BRCA2 protein (p.Val1711Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141863). 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 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.

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