ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9700A>G (p.Met3234Val) (rs730881574)

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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 RCV000568321 SCV000661212 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000568321 SCV000684087 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
GeneDx RCV000160177 SCV000210515 uncertain significance not provided 2014-09-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9700A>G at the cDNA level, p.Met3234Val (M3234V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met3234Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Met3234Val occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Met3234Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000552490 SCV000635755 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 3234 of the BRCA2 protein (p.Met3234Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs730881574, ExAC 0.006%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182266). 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 tolerated, but 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.

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