ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.338G>A (p.Arg113Lys) (rs876659161)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215283 SCV000275287 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-19 criteria provided, single submitter clinical testing
GeneDx RCV000478500 SCV000571999 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.338G>A at the cDNA level, p.Arg113Lys (R113K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 566G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an individual with squamous cell lung cancer and another with prostate cancer (Hovelson 2015, Paik 2015). BRCA2 Arg113Lys was not observed in large population cohorts (Lek 2016). Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg113Lys is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Arg113Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637720 SCV000759193 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 113 of the BRCA2 protein (p.Arg113Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. 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: 231439). 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 lysine 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.

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