ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1061C>T (p.Ala354Val) (rs761770500)

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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 RCV000165273 SCV000215990 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000165273 SCV000686316 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
GeneDx RCV000235923 SCV000293663 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1061C>T at the cDNA level, p.Ala354Val (A354V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant was observed in a patient with epithelial ovarian cancer (Song 2015). RAD51C Ala354Val 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 Ala354Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000541210 SCV000650002 uncertain significance Fanconi anemia, complementation group O 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 354 of the RAD51C protein (p.Ala354Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs761770500, ExAC 0.003%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 185785). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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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