Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000212901 | SCV000149855 | uncertain significance | not provided | 2013-12-20 | criteria provided, single submitter | clinical testing | RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.265G>A at the cDNA(V89I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Val89Ile was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. |
| Ambry Genetics | RCV000115946 | SCV000186641 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-13 | criteria provided, single submitter | clinical testing | The p.V89I variant (also known as c.265G>A), located in coding exon 3 of the RAD50 gene, results from a G to A substitution at nucleotide position 265. The valine at codon 89 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000115946 | SCV000260838 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 89 of the RAD50 protein (p.Val89Ile). This variant is present in population databases (rs151109830, gnomAD 0.04%). 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: 128010). 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 with a negative predictive value of 80%. 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. |
| Fulgent Genetics, |
RCV002483187 | SCV002783885 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2022-02-18 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV002483187 | SCV004207324 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2023-10-10 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000212901 | SCV004220089 | uncertain significance | not provided | 2022-06-09 | criteria provided, single submitter | clinical testing | In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). The frequency of this variant in the general population, 0.0004 (10/25124 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |