ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.434G>A (p.Arg145His) (rs147264215)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166844 SCV000217658 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166844 SCV000686456 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590143 SCV000859941 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing
GeneDx RCV000590143 SCV000565465 uncertain significance not provided 2018-06-03 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.434G>A at the cDNA level, p.Arg145His (R145H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in the mosaic state in at least one individual undergoing multi-gene hereditary cancer panel testing (Mu 2016). RAD51D Arg145His was observed at an allele frequency of 0.05% (13/24,016) in individuals of African ancestry 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, support a deleterious effect. Based on currently available evidence, it is unclear whether RAD51D Arg145His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590143 SCV000698104 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.434G>A (p.Arg145His) variant located in the P-loop containing nucleoside triphosphate hydrolase and C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 6/121410 (1/20242), which does not exceed the estimated maximal expected allele frequency for a pathogenic RAD51D variant of 1/8000. One clinical diagnostic laboratory has classified this variant as uncertain significance. The variant of interest has been reported in at least one patient sample referred for NGS-based multigene hereditary-cancer testing without strong evidence for causality (Mu_2016). Taken together, the variant is classified as a variant of uncertain significance (VUS), until additional information becomes available.
Invitae RCV000469434 SCV000551361 uncertain significance Breast-ovarian cancer, familial 4 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 145 of the RAD51D protein (p.Arg145His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs147264215, ExAC 0.06%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 187149). 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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