ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.629C>A (p.Ala210Glu) (rs376855484)

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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 RCV000575046 SCV000671941 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000575046 SCV000686476 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
GeneDx RCV000485736 SCV000565469 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.629C>A at the cDNA level, p.Ala210Glu (A210E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCG>GAG). This variant has been observed in at least one individual with breast cancer (Hauke 2018). RAD51D Ala210Glu 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 Ala210Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781798 SCV000920127 uncertain significance not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.629C>A (p.Ala210Glu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/246188 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000475295 SCV000551365 uncertain significance Breast-ovarian cancer, familial 4 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 210 of the RAD51D protein (p.Ala210Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs376855484, ExAC 0.003%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 410563). 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.

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