Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164282 | SCV000214909 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-05-01 | criteria provided, single submitter | clinical testing | The p.S447L variant (also known as c.1340C>T), located in coding exon 9 of the RAD50 gene, results from a C to T substitution at nucleotide position 1340. The serine at codon 447 is replaced by leucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.006% (greater than 15000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.S447L remains unclear.​ |
| Invitae | RCV000164282 | SCV002185837 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-04 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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: 184939). 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. 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. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 447 of the RAD50 protein (p.Ser447Leu). |