ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.620C>G (p.Ser207Trp) (rs370228071)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563013 SCV000663838 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-15 criteria provided, single submitter clinical testing The p.S207W variant (also known as c.620C>G), located in coding exon 7 of the RAD51D gene, results from a C to G substitution at nucleotide position 620. The serine at codon 207 is replaced by tryptophan, an amino acid with highly dissimilar properties. Extensive studies on another alteration at this same amino acid position (p.S207L) showed segregation with breast or ovarian cancer in four families, a strong association with ovarian cancer in a case-control study (P=2x10-6), and impaired homologous recombination, XRCC2 binding, and RAD51 foci formation in functional studies (Rivera B et al. Cancer Res., 2017 Aug;77:4517-4529). This alteration is located in the highly conserved Walker B motif of the RAD51D protein that is required for ATPase function and XRCC2 binding (Wiese C et al. Nucleic Acids Res., 2006 May;34:2833-43). This amino acid position is highly conserved in available vertebrate species, and was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneKor MSA RCV000563013 SCV000822182 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV001068462 SCV001233575 uncertain significance Breast-ovarian cancer, familial 4 2019-01-15 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 207 of the RAD51D protein (p.Ser207Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 480538). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This variant disrupts the p.Ser207 amino acid residue in RAD51D. Other variant(s) that disrupt this residue have been observed in individuals with RAD51D-related conditions (PMID: 28646019, 22986143, 26976419, 26845104, 21822267, 25186627), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194377 SCV001363869 uncertain significance not specified 2019-02-01 criteria provided, single submitter clinical testing Variant summary: RAD51D c.620C>G (p.Ser207Trp) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 277166 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.620C>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000563013 SCV001735565 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-13 criteria provided, single submitter clinical testing This missense variant replaces serine with tryptophan at codon 207 of the RAD51D protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. A different variant affecting the same codon, p.Ser207Leu, is considered to be disease-causing (ClinVar variation ID 142102 and PMID 28646019). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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