Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001999249 | SCV002287416 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 4 | 2022-01-16 | criteria provided, single submitter | clinical testing | 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. 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. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 32068069). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp268Glyfs*42) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the RAD51D protein. |
| Ambry Genetics | RCV002423220 | SCV002679829 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-25 | criteria provided, single submitter | clinical testing | The c.801delC variant, located in coding exon 9 of the RAD51D gene, results from a deletion of one nucleotide at nucleotide position 801, causing a translational frameshift with a predicted alternate stop codon (p.W268Gfs*42). This alteration occurs at the 3' terminus of theRAD51D gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 61 amino acids of the protein. However, premature stop codons are typically deleterious in nature, and internal structural analysis indicates W268Gfs*42 disrupts the ATP cap motif in RAD51D, which would disrupt its ability to form filaments and subsequent DNA repair activity (Wu Y et al. J Biol Chem, 2005 Jan;280:722-8; Amunugama R et al. J Biol Chem, 2012 Mar;287:8724-36; Amunugama R et al. DNA Repair (Amst), 2013 Sep;12:723-32; Ambry internal data). This alteration was detected in an individual with bilateral breast cancer diagnosed at age 38 (Kwong A et al. J Mol Diagn, 2020 04;22:544-554). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |