ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1090A>G (p.Ser364Gly) (rs587782565)

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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 RCV000131788 SCV000186837 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000232947 SCV000291211 uncertain significance Fanconi anemia, complementation group O 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 364 of the RAD51C protein (p.Ser364Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 22476429), as well as a healthy control individual (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 142585). 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.
Color RCV000131788 SCV000292215 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000482155 SCV000572601 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1090A>G at the cDNA level, p.Ser364Gly (S364G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). This variant has been observed in at least one breast cancer patient with a family history of breast and/or ovarian cancer, but in a case-control study, was absent in 3429 ovarian cancer patients and present in 1/2772 controls (Lu 2012, Song 2015). RAD51C Ser364Gly 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Ser364Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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