Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165926 | SCV000216681 | likely benign | Hereditary cancer-predisposing syndrome | 2018-09-18 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Invitae | RCV000165926 | SCV000289028 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 69 of the RAD50 protein (p.Asp69Asn). This variant is present in population databases (rs370769989, gnomAD 0.005%). 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: 186347). 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 with a positive 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003477622 | SCV004219300 | uncertain significance | not provided | 2023-08-19 | criteria provided, single submitter | clinical testing | In a large case-control study, this variant has been reported in one individual with breast cancer and none of the unaffected controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). The frequency of this variant in the general population, 0.000044 (5/113348 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. |