ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4579G>A (p.Ala1527Thr) (rs879254071)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235783 SCV000293359 uncertain significance not provided 2015-10-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4579G>A at the cDNA level, p.Ala1527Thr (A1527T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 4807G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala1527Thr 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 Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala1527Thr occurs at a position that is conserved across species and is located in the BRC repeats and the region of interaction with Rad51 and POLH that is required for stimulation of POLH DNA polymerization activity (Roy 2012, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ala1527Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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