Submissions for variant NM_005732.4(RAD50):c.3455G>A (p.Arg1152Gln)

gnomAD frequency: 0.00025  dbSNP: rs144253015

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212924	SCV000149865	uncertain significance	not provided	2014-01-09	criteria provided, single submitter	clinical testing	RAD50 has only been recently described in association with cancer predisposition and the risks are not well understood.This variant is denoted RAD50 c.3455G>A at the cDNA level, p.Arg1152Gln (R1152Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg1152Gln was observed with an allele frequency of 0.2% (11/4406) in African Americans in the NHLBI Exome Sequencing Project, which is not frequent enough to be considered a common benign variant. This variant is a semi-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is fully conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function but lean toward benign. The currently available evidence about this variant does not allow us to predict whether RAD50 Arg1152Gln is a pathogenic variant or a benign variant, and it is therefore classified as having unknown significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics	RCV000115956	SCV000186422	benign	Hereditary cancer-predisposing syndrome	2016-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000115956	SCV000261069	likely benign	Hereditary cancer-predisposing syndrome	2024-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824612	SCV002074405	likely benign	not specified	2022-01-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257410	SCV002538503	uncertain significance	Nijmegen breakage syndrome-like disorder	2021-08-23	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003398715	SCV004120265	uncertain significance	RAD50-related disorder	2022-09-29	criteria provided, single submitter	clinical testing	The RAD50 c.3455G>A variant is predicted to result in the amino acid substitution p.Arg1152Gln. This variant was reported in an individual with breast or Lynch syndrome (Table S1 - Velázquez et al. 2020. PubMed ID: 32522261). This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-131972872-G-A). In ClinVar this variant has conflicting interpretations of pathogenicity of benign, likely benign, and uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/128019/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212924	SCV004220103	likely benign	not provided	2023-06-30	criteria provided, single submitter	clinical testing