ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.620C>T (p.Ser207Leu) (rs370228071)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130934 SCV000185846 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Deficient protein function in appropriate functional assay(s),Significant disease association in appropriately sized case-control study(ies),Structural Evidence
Color RCV000130934 SCV000686475 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
Counsyl RCV000204202 SCV000786574 likely pathogenic Breast-ovarian cancer, familial 4 2018-05-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000204202 SCV000611514 uncertain significance Breast-ovarian cancer, familial 4 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000590382 SCV000292679 likely pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.620C>T at the cDNA level, p.Ser207Leu (S207L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been observed in individuals with primary peritoneal, breast, and/or ovarian cancer and co-segregated with ovarian cancer in at least two families (Loveday 2011, Wickramanayake 2012, Golmard 2013, Shirts 2016, Tung 2015, Rivera 2017). Rivera et al. (2017) identified this variant in 3.81% of high grade serous ovarian cancer cases and 0.2% of unaffected controls in the French Canadian population. Functional analyses demonstrate this variant impairs homologous recombination activity (Rivera 2017). RAD51D Ser207Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain and the Walker B motif (Miller 2004, Wiese 2006). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider RAD51D Ser207Leu to be likely pathogenic.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000130934 SCV000576437 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000722123 SCV000698110 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-09 criteria provided, single submitter clinical testing Variant summary: RAD51D c.620C>T (p.Ser207Leu) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal and AAA+ ATPase domains 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 2.9e-05 in 279286 control chromosomes (gnomAD and publication). The variant, c.620C>T, has been reported in the literature in multiple individuals affected with Breast, Endometrial and Ovarian Cancer (Gomard_2013, Loveday_2011, Rivera_2017, Shirts_2015, Tung_2016, Wickramanyake_2012). This variant was reported as being highly prevalent in French Canadians and as being associated with a high risk for ovarian high-grade serous carcinoma (HGSC) (3.8% cases vs. 0.2% controls), but was not associated with risk for breast, endometrial, pancreas or colorectal cancers (Rivera_2017). The authors conclude this variant as a bona fide pathogenic RAD51D missense cancer susceptibility allele and is one of the most frequently observed alleles conferring high risk of ovarian high-grade serous carcinoma (HGSC) in the French Canadian population of Quebec. The variant was shown functionally to disrupt the RAD51D-XRCC2 interaction, and impair homologous recombination (Rivera_2017). It also conferred sensitivity to PARP-inhibitor therapies. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 likely pathogenic and 5 VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000204202 SCV000261711 likely pathogenic Breast-ovarian cancer, familial 4 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 207 of the RAD51D protein (p.Ser207Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs370228071, ExAC 0.006%). This variant has been reported to segregate with ovarian and endometrial cancer in two families (PMID: 28646019). In addition, it has been reported in unrelated individuals affected with ovarian cancer, peritoneal carcinoma, and breast cancer (PMID: 22986143, 26976419, 26845104, 21822267, 28646019, 25186627). ClinVar contains an entry for this variant (Variation ID: 142102). This missense change occurs within the conserved RAD51D Walker B domain (amino acid residues 202-207), which has been shown to be necessary for RAD51D to interact with XRCC2 and RAD51C, and for efficient homologous recombinational repair (PMID: 16717288). An experimental study has shown that this missense change disrupts the interaction between RAD51D and XRCC2, causing impaired homologous recombination (PMID: 28646019). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000130934 SCV000266230 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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