Submissions for variant NM_005732.4(RAD50):c.2468G>A (p.Arg823Gln)

gnomAD frequency: 0.00001  dbSNP: rs572533256

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196757	SCV000254887	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 823 of the RAD50 protein (p.Arg823Gln). This variant is present in population databases (rs572533256, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 216623). 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 expected to disrupt RAD50 protein function with a positive 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.
Ambry Genetics	RCV000196757	SCV000663605	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	The p.R823Q variant (also known as c.2468G>A), located in coding exon 15 of the RAD50 gene, results from a G to A substitution at nucleotide position 2468. The arginine at codon 823 is replaced by glutamine, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781778	SCV000920103	likely benign	not specified	2017-11-24	criteria provided, single submitter	clinical testing	Variant summary: The RAD50 c.2468G>A (p.Arg823Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 21/276876 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.000552 (17/30772). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. One clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Revvity Omics, Revvity	RCV003485560	SCV004236533	uncertain significance	Nijmegen breakage syndrome-like disorder	2023-06-08	criteria provided, single submitter	clinical testing