ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.26G>C (p.Cys9Ser) (rs140825795)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587404 SCV000149721 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.26G>C at the cDNA level, p.Cys9Ser (C9S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>TCC). RAD51D Cys9Ser has been reported in numerous patients with breast, ovarian, or colorectal cancer, as well as in at least four controls (Loveday 2011, Wickramanayake 2012, Golmard 2013, Gutierrez-Enriquez 2014, Song 2015, Tung 2015, Yurgelun 2017, Hauke 2018). This variant was also observed in a woman from a cohort of unselected ovarian cancer cases whose tumor showed loss of heterozygosity, suggesting this variant may have been related to tumorigenesis in that patient (Wickramanayake 2012). RAD51D Cys9Ser was observed at an allele frequency of 0.07% (88/124,366) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located within the ssDNA and XRCC2 binding domains (Miller 2004, Kim 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51D Cys9Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115812 SCV000185831 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000231466 SCV000287702 likely benign Breast-ovarian cancer, familial 4 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000231466 SCV000488471 uncertain significance Breast-ovarian cancer, familial 4 2016-06-09 criteria provided, single submitter clinical testing
Color RCV000115812 SCV000537513 likely benign Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587404 SCV000602155 uncertain significance not provided 2018-12-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175378 SCV000698094 likely benign not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: RAD51D c.26G>C (p.Cys9Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 258298 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is benign. The variant, c.26G>C, has been reported in the literature in individuals affected with Breast and Ovarian Cancer or other cancers and also in controls (Wickramanyake_2012, Gutirrez-Enrquez_2013, Loveday_2011, Golmard_2013, Song_2015, Yurgelun_2017, Tung_2015, Madeddu_2019). In addition, this variant has been reported in 10/9884 individuals who are at least 70 years old and cancer-free. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.5851_5854del, p.Ser1951Trpfs*11, Tung_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587404 SCV000806577 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing
Mendelics RCV000709461 SCV000839205 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587404 SCV000861249 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing

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