Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164239 | SCV000214862 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-28 | criteria provided, single submitter | clinical testing | The p.R87C variant (also known as c.259C>T), located in coding exon 3 of the RAD50 gene, results from a C to T substitution at nucleotide position 259. The arginine at codon 87 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000164239 | SCV000259547 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 87 of the RAD50 protein (p.Arg87Cys). This variant is present in population databases (rs143802516, gnomAD 0.03%). 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: 184899). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781780 | SCV000920105 | uncertain significance | not specified | 2022-07-04 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.259C>T (p.Arg87Cys) results in a non-conservative amino acid change located in the Rad50/SbcC-type AAA domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 282706 control chromosomes, predominantly at a frequency of 0.00032 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.259C>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV002478501 | SCV002774717 | uncertain significance | not provided | 2022-09-02 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.00032 (8/24962 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant was found both in individuals with breast cancer as well as healthy individuals in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD50). 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Prevention |
RCV003416034 | SCV004118522 | uncertain significance | RAD50-related condition | 2022-09-27 | criteria provided, single submitter | clinical testing | The RAD50 c.259C>T variant is predicted to result in the amino acid substitution p.Arg87Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131911514-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184899/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Baylor Genetics | RCV003467287 | SCV004207326 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2023-10-09 | criteria provided, single submitter | clinical testing |