ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.428A>G (p.Gln143Arg) (rs587780255)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116174 SCV000186234 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116174 SCV000686351 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Counsyl RCV000663261 SCV000786489 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000200995 SCV000150083 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.428A>G at the cDNA level, p.Gln143Arg (Q143R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). RAD51C Gln143Arg has been reported in several individuals with breast or ovarian cancer (Romero 2011, Loveday 2012, Osorio 2012, Norquist 2016, Tung 2016, Neidhardt 2017). While Osorio et al. (2012) concluded that RAD51C Gln143Arg was not able to restore RAD51 foci formation at levels similar to wild-type in RAD51C-deficient fibroblasts, the results are described as intermediate. Furthermore, RAD51C protein levels were not evaluated in this study; therefore, these results could represent differential protein expression rather than reduced functionality. Another functional study found that cells expressing this variant demonstrated significantly reduced homologous recombination activity, increased sensitivity to Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors compared to wild-type, and failure to suppress G2/M accumulation, but was able to retain stability (Somyajit 2015). RAD51C Gln143Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Gln143Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000123374 SCV000166697 uncertain significance Fanconi anemia, complementation group O 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 143 of the RAD51C protein (p.Gln143Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs587780255, ExAC 0.007%). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 22451500, 22538716, 21537932, 26976419, 26720728). It has also been reported in a family affected with breast cancer. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 26740214). ClinVar contains an entry for this variant (Variation ID: 128205). Experimental studies have shown that the functional activity of the RAD51C protein carrying this variant is reduced relative to the wild-type protein (PMID: 22451500). In addition, complementation studies in RAD51-deficient cells show that this variant exhibits reduced homologous recombination activity, increased sensitivity to poly (ADP-ribose) polymerase 1 inhibitors, and a failure to suppress cell cycle G2/M accumulation compared to the wild-type RAD51 protein (PMID: 25292178). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200995 SCV000888598 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing

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