ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.934C>T (p.Arg312Trp) (rs730881932)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563267 SCV000674683 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000563267 SCV000686405 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000160924 SCV000211628 uncertain significance not provided 2015-05-18 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.934C>T at the cDNA level, p.Arg312Trp (R312W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Arg312Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Arg312Trp occurs at a position that is conserved in mammals and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51C Arg312Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781796 SCV000920123 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-20 criteria provided, single submitter clinical testing Variant summary: RAD51C c.934C>T (p.Arg312Trp) 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 247446 control chromosomes (gnomAD and publications). c.934C>T has been reported in the literature in individuals affected with ovarian cancer (Gayarre_2017). Specifically, Gayarre_2017 identified the variant in two siblings with personal history of ovarian cancer and determined through segregation analysis that the variant was inherited from their mother (obligate carrier) who also was affected with ovarian cancer. These data indicate that the variant may be associated with disease. Gayarre_2017 also carried out multiple functional assays demonstrating 1. decreased cell survival in response to DNA interstrand cross-linking agents such as Mitomycin C, 2. failure to rescue G2/M cell cycle arrest, 3. increased levels of DNA damage marker pH2AX, 4. reduced RAD51 foci formation at sites of DSB and 5. failure to rescue chromosomal instability in RAD51C-deficient cells. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance, however these classifications were done prior to the Gayarre_2017 publication. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000807077 SCV000947109 uncertain significance Fanconi anemia, complementation group O 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 312 of the RAD51C protein (p.Arg312Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with ovarian cancer (PMID: 28829762). ClinVar contains an entry for this variant (Variation ID: 182836). An experimental study has shown that this missense change results in reduced DNA repair activity, abnormal RAD51 foci formation upon irradiation and higher chromosomal instability in vitro (PMID: 28829762). 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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