Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129203 | SCV000183947 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-29 | criteria provided, single submitter | clinical testing | The p.R1279H variant (also known as c.3836G>A), located in coding exon 25 of the RAD50 gene, results from a G to A substitution at nucleotide position 3836. The arginine at codon 1279 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in multiple individuals diagnosed with breast and/or ovarian cancer (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58; Kim H et al. Breast Cancer Res Treat, 2017 01;161:95-102; Nunziato M et al. Front Med (Lausanne), 2022 Aug;9:894358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000129203 | SCV000289069 | uncertain significance | Hereditary cancer-predisposing syndrome | 2025-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1279 of the RAD50 protein (p.Arg1279His). This variant is present in population databases (rs375710541, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 24894818, 27783279). ClinVar contains an entry for this variant (Variation ID: 140931). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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, |
RCV000765811 | SCV000897201 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998254 | SCV005625164 | uncertain significance | not provided | 2024-02-20 | criteria provided, single submitter | clinical testing | The RAD50 c.3836G>A (p.Arg1279His) variant has been reported in the published literature in individuals with breast cancer (PMID: 27783279 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)). The frequency of this variant in the general population, 0.000062 (8/129038 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. |