ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.640C>T (p.Arg214Cys) (rs140804406)

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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 RCV000129799 SCV000184609 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129799 SCV000903132 likely benign Hereditary cancer-predisposing syndrome 2016-01-05 criteria provided, single submitter clinical testing
Counsyl RCV000662365 SCV000784752 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2017-11-13 criteria provided, single submitter clinical testing
GeneDx RCV000212945 SCV000211616 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.640C>T at the cDNA level, p.Arg214Cys (R214C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported in individuals with breast cancer or endometrial cancer (Clague 2011, Tung 2015, Ring 2016). Yeast two-hybrid analysis demonstrated significant reductions in interaction between RAD51C Arg214Cys and both XRCC3 and RAD51B; however there were no changes in the steady-state levels of RAD51C (Clague 2011). RAD51C Arg214Cys was observed at an allele frequency of 0.06% (15/24,028) in individuals of African ancestry in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Arg214Cys is located within the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Arg214Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781795 SCV000920122 uncertain significance not specified 2018-11-20 criteria provided, single submitter clinical testing Variant summary: RAD51C c.640C>T (p.Arg214Cys) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 276970 control chromosomes, predominantly at a frequency of 0.00062 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51C causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.640C>T, has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Tung_2014, Ring_2016, Clague_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. Small but significant reductions in interaction between RAD51C and both XRCC3 and RAD51B were observed, but there were no marked changes in the steady-state level of RAD51C (Clague_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000204512 SCV000261245 uncertain significance Fanconi anemia, complementation group O 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 214 of the RAD51C protein (p.Arg214Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs140804406, ExAC 0.03%). This variant has been reported in individuals affected with breast and endometrial cancer (PMID: 21980511, 25186627, 27443514). ClinVar contains an entry for this variant (Variation ID: 141324). Experimental studies in yeast have shown that this missense change mildly reduces RAD51C binding to XRCC1 and RAD51B. The clinical significance of these findings is unclear (PMID: 21980511). 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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