Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000233503 | SCV000273819 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-01-21 | criteria provided, single submitter | clinical testing | The p.N38S variant (also known as c.113A>G), located in coding exon 1 of the RAD50 gene, results from an A to G substitution at nucleotide position 113. The asparagine at codon 38 is replaced by serine, an amino acid with highly similar properties. This variant was reported in 1/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16(3):R58). This amino acid position is highly 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 | RCV000233503 | SCV000288996 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-27 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 38 of the RAD50 protein (p.Asn38Ser). This variant is present in population databases (rs750480943, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818, 30613976). ClinVar contains an entry for this variant (Variation ID: 230314). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. |