ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.134A>G (p.Glu45Gly) (rs587781383)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129215 SCV000183965 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000167882 SCV000218528 uncertain significance Fanconi anemia, complementation group O 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 45 of the RAD51C protein (p.Glu45Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs587781383, ExAC 0.009%). This variant has been reported in an individual affected with kidney clear cell carcinoma (PMID: 26689913), and an individual affected with breast cancer, although the significance of this finding is uncertain as family members were not tested to determine if the variant segregated with disease (PMID: 21537932). ClinVar contains an entry for this variant (Variation ID: 140940). 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. 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.
Counsyl RCV000167882 SCV000490023 uncertain significance Fanconi anemia, complementation group O 2016-10-05 criteria provided, single submitter clinical testing
Counsyl RCV000409379 SCV000490024 uncertain significance Breast-ovarian cancer, familial 3 2016-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000588471 SCV000568049 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.134A>G at the cDNA level, p.Glu45Gly (E45G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant has been reported in at least one woman with a history of breast cancer and in an individual with clear cell renal cell carcinoma (Osorio 2012, Lu 2015). RAD51C Glu45Gly was observed at an allele frequency of 0.11% (11/9,850) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the region that is required for Holliday junction resolution activity (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Glu45Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588471 SCV000699795 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.134A>G (p.Glu45Gly) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population ExAC with an allele frequency of 6/121166 (1/20193), predominantly in the European (Non-Finnish) cohort, 6/66588 (1/11097), which slightly exceeds the estimated maximal expected allele frequency of a pathogenic RAD51C variant of 1/16000. However, this observation needs to be cautiously considered due to the cohort could harbor individuals with a potential RAD51C phenotype. In addition, multiple publications have cited the variant in affected individuals, although with limited information (ie, lack of co-occurrence and cosegregation data). Furthermore, multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588471 SCV000889814 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing
Color RCV000129215 SCV000902786 likely benign Hereditary cancer-predisposing syndrome 2016-01-02 criteria provided, single submitter clinical testing

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