ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.137C>G (p.Ser46Cys) (rs587780102)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212953 SCV000604997 uncertain significance not specified 2016-11-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115808 SCV000185614 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115808 SCV000686419 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Counsyl RCV000228533 SCV000784997 uncertain significance Breast-ovarian cancer, familial 4 2017-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000656964 SCV000149717 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.137C>G at the cDNA level, p.Ser46Cys (S46C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has been reported in at least one individual with ovarian cancer and another with a personal and family history of breast cancer (Wickramanayake 2012, Kraus 2017). RAD51D Ser46Cys was observed at an allele frequency of 0.02% (20/126,540) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in 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 Ser46Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228533 SCV000287698 uncertain significance Breast-ovarian cancer, familial 4 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 46 of the RAD51D protein (p.Ser46Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs587780102, ExAC 0.02%), 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 breast cancer (PMID: 22986143, 27616075), and an individual affected with multiple adenomatous polyps (PMID: 25938944). ClinVar contains an entry for this variant (Variation ID: 127882). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000709453 SCV000839197 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing

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