ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.797G>A (p.Arg266His) (rs779808083)

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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 RCV000165809 SCV000216556 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000165809 SCV000908948 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing
GeneDx RCV000487018 SCV000566809 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.797G>A at the cDNA level, p.Arg266His (R266H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Arg266His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. RAD51D Arg266His occurs at a position that is conserved in mammals and is located in the RAD51C binding domain (Miller 2004). 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 Arg266His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000458653 SCV000551374 uncertain significance Breast-ovarian cancer, familial 4 2018-08-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 266 of the RAD51D protein (p.Arg266His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs779808083, ExAC 0.01%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 186248). 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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