ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3176T>G (p.Leu1059Arg) (rs1064793927)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486653 SCV000567364 uncertain significance not provided 2017-12-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3176T>G at the cDNA level, p.Leu1059Arg (L1059R) at the protein level, and results in the change of a Leucine to an Arginine (CTG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 3404T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1059Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu1059Arg is located within the RAD51 interaction domain (Roy 2012). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether BRCA2 Leu1059Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000576066 SCV000668844 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000691591 SCV000819377 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 1059 of the BRCA2 protein (p.Leu1059Arg). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and arginine. 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: 419515). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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