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

gnomAD frequency: 0.00009  dbSNP: rs200017020

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Ambry Genetics	RCV000115928	SCV000183750	likely benign	Hereditary cancer-predisposing syndrome	2019-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000115928	SCV000254874	likely benign	Hereditary cancer-predisposing syndrome	2023-12-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000409378	SCV000489005	uncertain significance	Nijmegen breakage syndrome-like disorder	2016-08-01	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030502	SCV001193702	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV001818281	SCV002070057	uncertain significance	not specified	2020-01-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RAD50 gene demonstrated a sequence change, c.1211A>G, in exon 8 that results in an amino acid change, p.Gln404Arg. This sequence change does not appear to have been previously described in patients with RAD50-related disorders and has been described in the gnomAD database with a low population frequency of 0.16% in East Asian subpopulation (dbSNP rs200017020). The p.Gln404Arg change affects a moderately conserved amino acid residue located in a domain of the RAD50 protein that is known to be functional. The p.Gln404Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gln404Arg change remains unknown at this time.
Sema4, Sema4	RCV000409378	SCV002538445	uncertain significance	Nijmegen breakage syndrome-like disorder	2021-07-14	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212908	SCV004219272	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894952	SCV004717356	likely benign	RAD50-related condition	2021-04-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).