ClinVar Miner

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

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Total submissions: 4
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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 Insufficient evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Well-characterized mutation at same position;Structural Evidence
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 C15"). 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.
Integrated Genetics/Laboratory Corporation of America 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.

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