Submissions for variant NM_005732.4(RAD50):c.2288G>A (p.Arg763His)

gnomAD frequency: 0.00026  dbSNP: rs141989813

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212915	SCV000149848	uncertain significance	not provided	2013-12-18	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.2288G>A at the cDNA level, p.Arg763His (R763H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg763His was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one positive polar amino acid for another, altering a position that is well conserved throughout evolution and is not located in a known functional domain. 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	RCV000115939	SCV000186090	likely benign	Hereditary cancer-predisposing syndrome	2018-09-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000115939	SCV000254885	likely benign	Hereditary cancer-predisposing syndrome	2025-01-13	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115939	SCV000822149	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212915	SCV002009651	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228349	SCV002511725	likely benign	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.2288G>A (p.Arg763His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 250948 control chromosomes, predominantly at a frequency of 0.00058 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 9.28 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. c.2288G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Bono_2021, Damiola_2014). These reports do 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. ClinVar contains an entry for this variant (Variation ID: 128003). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV001762238	SCV002538475	likely benign	Nijmegen breakage syndrome-like disorder	2021-05-03	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000212915	SCV004161372	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	RAD50: BP4
PreventionGenetics, part of Exact Sciences	RCV004751268	SCV005353862	likely benign	RAD50-related disorder	2024-07-26	no assertion criteria provided	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).