ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.419G>A (p.Gly140Glu) (rs730881945)

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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 RCV000160940 SCV000216650 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588145 SCV000211647 uncertain significance not provided 2016-03-15 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.419G>A at the cDNA level, p.Gly140Glu (G140E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Gly140Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Gly140Glu occurs at a position that is conserved across species and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51D Gly140Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588145 SCV000698103 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The RAD51D c.419G>A (p.Gly140Glu) variant located in the DNA recombination and repair protein Rad51-like, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in 121410 control chromosomes (ExAC). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Although, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000535571 SCV000651745 uncertain significance Breast-ovarian cancer, familial 4 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 140 of the RAD51D protein (p.Gly140Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. 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 disease. ClinVar contains an entry for this variant (Variation ID: 182851). 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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