ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4781T>G (p.Met1594Arg) (rs730881533)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160079 SCV000210341 uncertain significance not provided 2014-05-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4781T>G at the cDNA level, p.Met1594Arg (M1594R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met1594Arg 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 Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Met1594Arg occurs at a position that is moderately conserved across species and is located in the BRC repeat domain that interacts with RAD51 (Roy 2012) and a region of interaction with POLH (UniProt). In addition, in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Met1594Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.

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