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
Ambry Genetics RCV000115812 SCV000185831 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Subpopulation frequency in support of benign classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000115812 SCV000537513 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587404 SCV000861249 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000587404 SCV000698094 likely benign not provided 2016-05-27 criteria provided, single submitter clinical testing Variant Summary: c.26G>C (p.Cys9Ser) is a missense mutation that occurs at a conserved position, and 4/4 in silico tools predict a damaging outcome (SNP&Go not captured here due to low relability index). Although being reported by reputable databases/diagnostic centers as a VUS, the observed allele frequency in the large and diverse ExAC cohort is 0.00035 (47/131676 chrs tested), which is nearly 3-fold greater than the maximal expected allele frequency for a pathogenic RAD51D variant (0.00012). This allele frequency highly suggests that this variant is a benign polymorphism. Although the variant has been cited in breast/ovarian cancer patients, co-segregation and co-occurrence information was not provided, and in one gastric cancer family, a MAP3k6 variant co-occurrence was identified that authors consider to be likely pathogenic (Gaston et al 2014). Taken together,the variant has been classified as Likely Benign.
Invitae RCV000231466 SCV000287702 uncertain significance Breast-ovarian cancer, familial 4 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 9 of the RAD51D protein (p.Cys9Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs140825795, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with ovarian and/or breast cancer (PMID: 22986143, 24130102, 26261251), as well as unaffected individuals (PMID: 26261251, 21822267). ClinVar contains an entry for this variant (Variation ID: 127886). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000709461 SCV000839205 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000587404 SCV000806577 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212952 SCV000602155 uncertain significance not specified 2016-10-26 criteria provided, single submitter clinical testing

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