ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2177G>A (p.Arg726His) (rs28903092)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212914 SCV000149846 uncertain significance not provided 2014-02-27 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.2177G>A at the cDNA level, p.Arg726His (R726H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in one individual with familial breast cancer (Tommiska 2006). RAD50 Arg726His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one positive polar amino acid for another, altering a position that is well conserved throughout evolution and is located in the Zinc-hook domain via UniProt. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. At 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. Of note, two deleterious RAD50 mutations on opposite chromosomes (in trans) have been reported to cause Nijmegen breakage-like disorder (Waltes 2009). Therefore, if these variants are in trans, and if this patient does not have a related congenital disorder, then at least one is likely benign. Parental or family testing could help determine whether the variants are in cis or trans.
Ambry Genetics RCV000115937 SCV000184077 likely benign Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;No disease association in small case-control study;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000115937 SCV000261760 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 726 of the RAD50 protein (p.Arg726His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28903092, ExAC 0.06%). This variant has been reported in individuals affected with breast cancer (PMID: 16385572, 25503501). ClinVar contains an entry for this variant (Variation ID: 128001). 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.
Fulgent Genetics,Fulgent Genetics RCV000515380 SCV000611512 uncertain significance Nijmegen breakage syndrome-like disorder 2017-05-23 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115937 SCV000822148 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Reproductive Development, Murdoch Childrens Research Institute RCV000766182 SCV000882516 uncertain significance Premature ovarian insufficiency 2018-01-11 no assertion criteria provided research

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.