Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000166756 | SCV000217568 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-11-02 | criteria provided, single submitter | clinical testing | The p.I227S variant (also known as c.680T>G), located in coding exon 5 of the RAD50 gene, results from a T to G substitution at nucleotide position 680. The isoleucine at codon 227 is replaced by serine, 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 40000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.I227S remains unclear. |
| Invitae | RCV000166756 | SCV000939109 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-04 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 227 of the RAD50 protein (p.Ile227Ser). This variant is present in population databases (rs786203447, gnomAD 0.003%). 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: 187068). 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. |