Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000212926 | SCV000149868 | uncertain significance | not provided | 2014-02-17 | criteria provided, single submitter | clinical testing | RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.3789G>C at the cDNA level, p.Gln1263His (Q1263H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has been seen in a male with a history of familial prostate cancer (Leongamornlert 2014). RAD50 Gln1263His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is fully conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. |
| Ambry Genetics | RCV000115959 | SCV000186546 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-09 | criteria provided, single submitter | clinical testing | The p.Q1263H variant (also known as c.3789G>C), located in coding exon 25 of the RAD50 gene, results from a G to C substitution at nucleotide position 3789. The glutamine at codon 1263 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in an individual from a cohort of 191 men with 3 or more cases of prostate cancer in their family (Leongamornlert D et al. Br. J. Cancer. 2014 Mar;110:1663-72). This amino acid position is highly 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. |
| Invitae | RCV000115959 | SCV000547979 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1263 of the RAD50 protein (p.Gln1263His). This variant is present in population databases (rs115706334, gnomAD 0.007%). This missense change has been observed in individual(s) with prostate cancer (PMID: 24556621). ClinVar contains an entry for this variant (Variation ID: 128022). 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 expected to disrupt RAD50 protein function with a positive 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. |
| Baylor Genetics | RCV004567027 | SCV005052644 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2023-12-29 | criteria provided, single submitter | clinical testing |