ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.68A>G (p.His23Arg) (rs990062370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566071 SCV000663810 likely benign Hereditary cancer-predisposing syndrome 2016-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
GeneDx RCV000485429 SCV000565901 uncertain significance not provided 2015-03-16 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.68A>G at the cDNA level, p.His23Arg (H23R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D His23Arg 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 Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. RAD51D His23Arg occurs at a position that is not conserved across species and is located within a region that preferentially binds ssDNA (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether RAD51D His23Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000547804 SCV000651772 uncertain significance Breast-ovarian cancer, familial 4 2018-02-20 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 23 of the RAD51D protein (p.His23Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. 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: 418673). 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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