ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.431C>T (p.Ser144Phe) (rs587781875)

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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 RCV000130201 SCV000185038 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000483361 SCV000567841 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.431C>T at the cDNA level, p.Ser144Phe (S144F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign germline variant. RAD51D Ser144Phe 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 Ser144Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130201 SCV000686455 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
Invitae RCV000649709 SCV000771541 uncertain significance Breast-ovarian cancer, familial 4 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 144 of the RAD51D protein (p.Ser144Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs587781875, ExAC 0.004%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 141609). 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: "Probably 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.

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