ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3779G>A (p.Arg1260His)

gnomAD frequency: 0.00001  dbSNP: rs367683141
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130882 SCV000185788 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-09 criteria provided, single submitter clinical testing The p.R1260H variant (also known as c.3779G>A), located in coding exon 25 of the RAD50 gene, results from a G to A substitution at nucleotide position 3779. The arginine at codon 1260 is replaced by histidine, an amino acid with highly similar properties. 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 (formerly Invitae), Labcorp RCV000130882 SCV000289066 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-03 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 1260 of the RAD50 protein (p.Arg1260His). This variant is present in population databases (rs367683141, gnomAD 0.03%). This missense change has been observed in individual(s) with RAD50-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 142065). 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.
GeneKor MSA RCV000130882 SCV000822156 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002478397 SCV002800859 uncertain significance Nijmegen breakage syndrome-like disorder 2021-10-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV002478397 SCV004207370 uncertain significance Nijmegen breakage syndrome-like disorder 2024-02-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477547 SCV004220116 uncertain significance not provided 2023-08-11 criteria provided, single submitter clinical testing In the published literature, the variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID: 31159747 (2019), 32658311 (2021)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD50)).The frequency of this variant in the general population, 0.00034 (12/35436 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GenomeConnect - Invitae Patient Insights Network RCV003483501 SCV004228750 not provided Nijmegen breakage syndrome-like disorder; Breast cancer, susceptibility to no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 09-24-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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