ClinVar Genomic variation as it relates to human health

This variant inserts 1 nucleotide in exon 7 of the RAD51D gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This sequence change creates a premature translational stop signal (p.Thr209Hisfs*118) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the RAD51D protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25452441, 26261251, 32107557). ClinVar contains an entry for this variant (Variation ID: 480540). This variant disrupts the ATPase domain and RAD51C interaction domain of the RAD51D protein, which are necessary for the DNA repair activity (PMID: 14704354, 19327148, 21111057, 10749867). While functional studies have not been performed to directly test the effect of this variant on RAD51D protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The c.623dupT variant, located in coding exon 7 of the RAD51D gene, results from a duplication of T at nucleotide position 623, causing a translational frameshift with a predicted alternate stop codon (p.T209Hfs*118). This alteration occurs at the 3' terminus of the RAD51D gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 120 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, structural analysis suggests that this frameshift would disrupt the ATPase functional domain (Amunugama R et al. J. Biol. Chem. 2012 Mar;287(12):8724-36). This alteration has been identified in high-risk breast/ovarian cancer families (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11). In another study this variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Based on the majority of available evidence to date, this variant is likely to be pathogenic.