ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.116C>T (p.Ala39Val) (rs398122724)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130510 SCV000185379 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130510 SCV000911388 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
Counsyl RCV000077656 SCV000785262 uncertain significance Breast-ovarian cancer, familial 2 2017-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000160132 SCV000210423 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.116C>T at the cDNA level, p.Ala39Val (A39V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 344C>T. This variant was observed in an individual with bilateral breast cancer and a thyroid tumor; however, testing for that individual identified additional variants in another cancer predisposition gene (Dominguez-Valentin 2017). BRCA2 Ala39Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with PALB2 (Roy 2012). 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 Ala39Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000545014 SCV000635144 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 39 of the BRCA2 protein (p.Ala39Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs398122724, ExAC 0.002%). This variant has been observed in an individual with breast cancer and neoplasm of the thyroid gland (PMID: 28608266). ClinVar contains an entry for this variant (Variation ID: 91748). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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) RCV000077656 SCV000109459 uncertain significance Breast-ovarian cancer, familial 2 2011-12-07 no assertion criteria provided clinical testing

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