Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000571424 | SCV000667160 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-23 | criteria provided, single submitter | clinical testing | The p.K235M variant (also known as c.704A>T), located in coding exon 8 of the RAD51D gene, results from an A to T substitution at nucleotide position 704. The lysine at codon 235 is replaced by methionine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000687592 | SCV000815168 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 4 | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 235 of the RAD51D protein (p.Lys235Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 482194). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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. |