ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9433G>A (p.Val3145Met) (rs587776476)

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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 RCV000217472 SCV000275245 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Counsyl RCV000144197 SCV000785310 uncertain significance Breast-ovarian cancer, familial 2 2017-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000486980 SCV000565721 uncertain significance not provided 2016-12-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9433G>A at the cDNA level, p.Val3145Met (V3145M) 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 9661G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val3145Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val3145Met occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information and internal data, it is unclear whether BRCA2 Val3145Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000227102 SCV000283367 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 3145 of the BRCA2 protein (p.Val3145Met). The valine residue is moderately 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 156180). 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 methionine 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.
Sharing Clinical Reports Project (SCRP) RCV000144197 SCV000189270 uncertain significance Breast-ovarian cancer, familial 2 2011-05-24 no assertion criteria provided clinical testing

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