ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.629C>T (p.Ala210Val) (rs376855484)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130714 SCV000185601 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000412230 SCV000489288 uncertain significance Breast-ovarian cancer, familial 4 2016-09-13 criteria provided, single submitter clinical testing
Color RCV000130714 SCV000537602 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing
Invitae RCV000412230 SCV000551348 uncertain significance Breast-ovarian cancer, familial 4 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 210 of the RAD51D protein (p.Ala210Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs376855484, ExAC 0.01%). This variant has been reported in individuals affected with ovarian cancer, breast cancer, and an individual undergoing Lynch syndrome testing (PMID: 24130102, 26057125, 26261251, 25452441, 25980754). ClinVar contains an entry for this variant (Variation ID: 141969). 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. 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.
GeneDx RCV000657049 SCV000567621 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.629C>T at the cDNA level, p.Ala210Val (A210V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has been reported in at least five individuals with breast and/or ovarian cancer (Gutierrez-Enriquez 2014, Couch 2015, Janatova 2015, Song 2015). It was also reported in at least one individual with early-onset colon cancer, in an individual with a personal history of a Lynch syndrome-associated cancer and/or colon polyps, and in an individual with a personal and family history of pancreatic cancer (Yurgelun 2015, Pearlman 2017, Chaffee 2018). RAD51D Ala210Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51D Ala210Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484961 SCV000602163 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000484961 SCV001338645 uncertain significance not specified 2020-04-13 criteria provided, single submitter clinical testing Variant summary: RAD51D c.629C>T (p.Ala210Val) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding 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 2.3e-05 in 257026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.629C>T has been reported in the literature in individuals affected with Breast/Ovarian Cancer Syndrome, Lynch syndrome, or pancreatic cancer (Gutierrez-Enrquez_2014, Couch_2015, Yurgelun_2015, Janatova_2015, Song_2015, Pearlman_2016, Chaffee_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 uncertain significance.

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