Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164950 | SCV000215641 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-26 | criteria provided, single submitter | clinical testing | The c.3164G>A variant (also known as p.S1055N), located in coding exon 20 of the RAD50 gene, results from a G to A substitution at nucleotide position 3164. This change occurs in the last base pair of coding exon 20, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the serine at codon 1055 to asparagine, an amino acid with highly similar properties. Both the nucleotide and amino acid positions are poorly conserved in available vertebrate species, with A being the reference allele and asparagine as the reference amino acid in the majority of mammals. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as missense variant, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000164950 | SCV000259244 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-09 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1055 of the RAD50 protein (p.Ser1055Asn). This variant also falls at the last nucleotide of exon 20, which is part of the consensus splice site for this exon. 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: 185510). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. |