Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000213459 | SCV000277846 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-10 | criteria provided, single submitter | clinical testing | The p.H1087R variant (also known as c.3260A>G), located in coding exon 21 of the RAD50 gene, results from an A to G substitution at nucleotide position 3260. The histidine at codon 1087 is replaced by arginine, an amino acid with highly similar properties. In one study, this variant was reported in 0/1313 early-onset breast cancer cases and 1/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This alteration was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 06;53:366-76). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000213459 | SCV000548000 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1087 of the RAD50 protein (p.His1087Arg). This variant is present in population databases (rs758983771, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 233472). 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 RAD50 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. |