ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs761770500
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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 RCV000165273 SCV000215990 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-17 criteria provided, single submitter clinical testing The p.A354V variant (also known as c.1061C>T), located in coding exon 9 of the RAD51C gene, results from a C to T substitution at nucleotide position 1061. The alanine at codon 354 is replaced by valine, an amino acid with similar properties. This alteration has been observed in one individual diagnosed with epithelial ovarian cancer (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). This variant was also reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000541210 SCV000650002 uncertain significance Fanconi anemia complementation group O 2023-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 354 of the RAD51C protein (p.Ala354Val). This variant is present in population databases (rs761770500, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 185785). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Diagnostics, LLC DBA Color Health RCV000165273 SCV000686316 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-03 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 354 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID 26261251). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51C_000223). This variant has been identified in 2/250548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4 RCV000165273 SCV002531786 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-05 criteria provided, single submitter curation
Baylor Genetics RCV004567264 SCV005053946 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 3 2024-02-21 criteria provided, single submitter clinical testing

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