Submissions for variant NM_005732.4(RAD50):c.671G>A (p.Arg224His)

gnomAD frequency: 0.00065  dbSNP: rs28903088

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000731878	SCV000149872	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including pancreatic, breast, and/or ovarian cancer (Heikkinen et al., 2003; Tommiska et al., 2006; Hu et al., 2016); This variant is associated with the following publications: (PMID: 26209080, 16385572, 20571869, 14684699, 16474176, 24093751, 24894818, 26314886, 33471991, 26517685, 26787654, 26822949, 26483394)
Ambry Genetics	RCV000115963	SCV000172920	benign	Hereditary cancer-predisposing syndrome	2015-04-06	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	RCV000115963	SCV000253471	likely benign	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000115963	SCV000267083	likely benign	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731878	SCV000859741	uncertain significance	not provided	2018-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174561	SCV001337722	benign	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.671G>A (p.Arg224His) results in a non-conservative amino acid change located in the AAA domain (IPR038729) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 395844 control chromosomes in the gnomAD database (v2.1 and v3.1 datasets), including 1 homozygote. The observed variant frequency is approximately 11-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 benign. The variant, c.671G>A, has been reported in the literature in individuals affected with breast or ovarian cancer, and other tumor phenotypes (e.g. Heikkinen_2003, Tommiska_2006, Damiola_2014, Lhota_2016, Hu_2016, Young_2016). However, in a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 130/60466 cases and 107/53461 controls, suggesting no increased risk association for the variant with the disease (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=1), likely benign (n=2) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000731878	SCV002009643	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001762239	SCV002538531	likely benign	Nijmegen breakage syndrome-like disorder	2021-10-25	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003925118	SCV004737487	likely benign	RAD50-related disorder	2019-10-07	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).