Submissions for variant NM_005732.4(RAD50):c.3230G>A (p.Arg1077Gln)

gnomAD frequency: 0.00005  dbSNP: rs104895051

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129882	SCV000184699	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.R1077Q variant (also known as c.3230G>A), located in coding exon 21 of the RAD50 gene, results from a G to A substitution at nucleotide position 3230. The arginine at codon 1077 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.
Invitae	RCV000129882	SCV000548058	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-24	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 1077 of the RAD50 protein (p.Arg1077Gln). This variant is present in population databases (rs104895051, gnomAD 0.008%). 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: 127004). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000129882	SCV001251933	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174803	SCV001338149	uncertain significance	not specified	2021-02-19	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.3230G>A (p.Arg1077Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251224 control chromosomes (gnomAD v2.1 exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3230G>A has been reported in the literature in at least one affected individual found during hereditary-cancer testing, however no disease phenotype was provided (Mu_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Harris Lab, University of Minnesota	RCV000114870	SCV000148765	not provided	not provided		no assertion provided	not provided
GenomeConnect - Invitae Patient Insights Network	RCV003483474	SCV004228832	not provided	Nijmegen breakage syndrome-like disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-13-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.