Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000130131 | SCV000184964 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-08 | criteria provided, single submitter | clinical testing | The p.R486C variant (also known as c.1456C>T), located in coding exon 10 of the RAD50 gene, results from a C to T substitution at nucleotide position 1456. The arginine at codon 486 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 5/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res., 2014 Jun;16:R58). This alteration was also reported in 1 of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutations (Kim H et al. Breast Cancer Res. Treat., 2017 01;161:95-102). This alteration was 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). Additionally, this variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).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 | RCV000130131 | SCV000628158 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 486 of the RAD50 protein (p.Arg486Cys). This variant is present in population databases (rs375218200, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818, 27783279). ClinVar contains an entry for this variant (Variation ID: 141555). 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. |