Submissions for variant NM_005732.4(RAD50):c.3036+5G>A

gnomAD frequency: 0.00078  dbSNP: rs181016343

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000115952	SCV000053552	likely benign	Hereditary cancer-predisposing syndrome	2021-11-04	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.
GeneDx	RCV000514683	SCV000149861	uncertain significance	not provided	2017-08-10	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 IVS19+5G>A, or c.3036+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 19 of the RAD50 gene. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 3036+5G>A occurs at a position that is well conserved throughout evolution. This particular nucleotide substitution was observed in multiple subpopulations, with the highest allele frequency of 0.09% (8/8588) in European Americans in the NHLBI Exome Sequencing Project. Multiple in silico splicing models predict a reduced likelihood that the nearby canonical donor splice site is utilized. At the molecular level, the impact of this missense variant on protein structure and function is not known and we consider this to be a variant of uncertain significance. Futhermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000115952	SCV000253464	benign	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203146	SCV000258028	uncertain significance	not specified	2015-03-06	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000115952	SCV000267085	uncertain significance	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000412309	SCV000489291	uncertain significance	Nijmegen breakage syndrome-like disorder	2016-09-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000203146	SCV000596682	uncertain significance	not specified	2016-06-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514683	SCV000610171	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115952	SCV000822153	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000412309	SCV000891635	benign	Nijmegen breakage syndrome-like disorder	2024-06-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203146	SCV000918115	likely benign	not specified	2017-11-20	criteria provided, single submitter	clinical testing	Variant summary: The RAD50 c.3036+5G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict a weakening effect on the canonical splicing donor site and 3/5 predict loss of a cryptic splicing donor site at the nucleotide of interest. However, these predictions have yet to be confirmed by functional studies. This variant was found in 352/276630 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.013132 (133/10128). This frequency is about 210 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 Ashkenazi Jewish origin. This variant has been reported in affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/VUS, all without evidence for independent evaluation. Taken together, this variant is currently classified as likely benign.
Mendelics	RCV000412309	SCV001136977	benign	Nijmegen breakage syndrome-like disorder	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000412309	SCV002538491	benign	Nijmegen breakage syndrome-like disorder	2020-08-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000514683	SCV002774230	likely benign	not provided	2022-09-26	criteria provided, single submitter	clinical testing