ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1211A>G (p.Gln404Arg) (rs200017020)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115928 SCV000183750 likely benign Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Counsyl RCV000409378 SCV000489005 uncertain significance Nijmegen breakage syndrome-like disorder 2016-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000212908 SCV000149837 uncertain significance not provided 2014-01-20 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.1211A>G at the cDNA level, p.Gln404Arg (Q404R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Gln404Arg was not observed at a significant allele frequency in 1000 Genomes, and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is moderately conserved throughout evolution and is located within a potential coiled coil region (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Invitae RCV000115928 SCV000254874 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 404 of the RAD50 protein (p.Gln404Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs200017020, ExAC 0.1%). This variant has been reported in an individual affected with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127992). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.