Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000167170 | SCV000218003 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-25 | criteria provided, single submitter | clinical testing | The p.L642V variant (also known as c.1924T>G), located in coding exon 12 of the RAD50 gene, results from a T to G substitution at nucleotide position 1924. The leucine at codon 642 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 4/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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 | RCV000167170 | SCV000547977 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 642 of the RAD50 protein (p.Leu642Val). This variant is present in population databases (rs201132221, 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: 187441). 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. |
| Cancer Genomics Group, |
RCV001030505 | SCV001193705 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003477635 | SCV004219296 | uncertain significance | not provided | 2023-05-05 | criteria provided, single submitter | clinical testing | In a breast cancer association study, the variant was observed in breast cancer cases as well as in control subjects (see LOVD (http://databases.lovd.nl/shared/genes/RAD50) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00027 (5/18390 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. |