ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.154A>C (p.Ile52Leu) (rs730881927)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563190 SCV000667110 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000563190 SCV000906586 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000160918 SCV000211622 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.154A>C at the cDNA level, p.Ile52Leu (I52L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>CTA). This variant has been observed in 1 out of 427 cancer-free control subjects but was not found among 1,655 women with a personal history of breast and/or ovarian cancer (Thompson 2012). RAD51C Ile52Leu was not observed in large population cohorts (Lek 2016). This variant is located within the region required for Holliday junction resolution activity (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether RAD51C Ile52Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000198840 SCV000255186 uncertain significance Fanconi anemia, complementation group O 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 52 of the RAD51C protein (p.Ile52Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (rs730881927, ExAC no frequency), but has been reported in the literature in an unaffected control individual (PMID: 21990120). ClinVar contains an entry for this variant (Variation ID: 182830). 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.

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