Submissions for variant NM_005732.4(RAD50):c.610A>G (p.Lys204Glu)

gnomAD frequency: 0.00006  dbSNP: rs202197835

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129161	SCV000183893	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	The p.K204E variant (also known as c.610A>G), located in coding exon 5 of the RAD50 gene, results from an A to G substitution at nucleotide position 610. The lysine at codon 204 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000129161	SCV000261148	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 204 of the RAD50 protein (p.Lys204Glu). This variant is present in population databases (rs202197835, gnomAD 0.01%). 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: 140908). 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 not expected to disrupt RAD50 protein function with a negative 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001261853	SCV001439195	uncertain significance	Nijmegen breakage syndrome-like disorder	2020-08-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226207	SCV003922978	likely benign	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.610A>G (p.Lys204Glu) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain (IPR038729) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250894 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.610A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 likely benign.
Baylor Genetics	RCV001261853	SCV004207320	uncertain significance	Nijmegen breakage syndrome-like disorder	2023-10-16	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483492	SCV004228872	not provided	Breast-ovarian cancer, familial, susceptibility to, 1; Nijmegen breakage syndrome-like disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-19-2020 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.