ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.73G>A (p.Gly25Arg) (rs80358961)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Breast Cancer Information Core (BIC) (BRCA2) RCV000113091 SCV000146109 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
GeneDx RCV000482909 SCV000568445 uncertain significance not provided 2016-05-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.73G>A at the cDNA level, p.Gly25Arg (G25R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 301G>A. This variant was observed in at least one individual who met NCCN guidelines for testing of the BRCA1 and BRCA2 genes (Kurian 2008). Although some functional studies show BRCA2 Gly25Arg diminishes PALB2 binding and DNA repair activity compared to wild-type, another assay demonstrates that this variant was able to rescue BRCA2 null embryonic stem cells from lethality similar to wild-type (Xia 2006, Biswas 2012). BRCA2 Gly25Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly25Arg occurs at a position that is conserved across species and is located in the PALB2 binding domain (Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gly25Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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