Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001981952 | SCV002217267 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-23 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1288 of the RAD50 protein (p.Arg1288Thr). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 1432184). |
| Ambry Genetics | RCV001981952 | SCV003855388 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-07 | criteria provided, single submitter | clinical testing | The p.R1288T variant (also known as c.3863G>C), located in coding exon 25 of the RAD50 gene, results from a G to C substitution at nucleotide position 3863. The arginine at codon 1288 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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. |
| Neuberg Centre For Genomic Medicine, |
RCV003339837 | SCV004046954 | uncertain significance | Nijmegen breakage syndrome-like disorder | criteria provided, single submitter | clinical testing | The c.3863G>C (p.Arg1288Thr) missense variant in RAD50 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn541Asp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 1288 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg1288Thr in RAD50 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). The above variant is present in heterozygous state and hence the molecular diagnosis is not confirmed. |