Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000462685 | SCV000548042 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 193 of the RAD50 protein (p.Arg193Trp). This variant is present in population databases (rs28903087, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 16385572, 20571869). ClinVar contains an entry for this variant (Variation ID: 408389). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Ambry Genetics | RCV000462685 | SCV000663675 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-12 | criteria provided, single submitter | clinical testing | The p.R193W variant (also known as c.577C>T), located in coding exon 5 of the RAD50 gene, results from a C to T substitution at nucleotide position 577. The arginine at codon 193 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in two European individuals with breast cancer as part of two separate case-control studies (Tommiska J et al. Int. J. Cancer. 2006 Jun;118:2911-6; Mosor M et al. Breast Cancer Res. Treat. 2010 Sep;123:607-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |