ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.412A>G (p.Asn138Asp) (rs141690729)

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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 RCV000160947 SCV000217873 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160947 SCV000686452 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-24 criteria provided, single submitter clinical testing
GeneDx RCV000586154 SCV000211654 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.412A>G at the cDNA level, p.Asn138Asp (N138D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. RAD51D Asn138Asp 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51D Asn138Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586154 SCV000698102 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.412A>G (p.Asn138Asp) variant located in the DNA recombination and repair protein Rad51-like, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 3/3 in silico tools (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 10/277158 control chromosomes at a frequency of 0.0000361, 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. 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 RCV000473960 SCV000551376 uncertain significance Breast-ovarian cancer, familial 4 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 138 of the RAD51D protein (p.Asn138Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs141690729, ExAC 0.006%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 182858). 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 tolerated, 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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