Submissions for variant NM_005591.4(MRE11):c.1783+5G>C

gnomAD frequency: 0.00284  dbSNP: rs142082313

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589610	SCV000149819	likely benign	not provided	2020-02-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115910	SCV000186079	benign	Hereditary cancer-predisposing syndrome	2014-11-24	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV001080166	SCV000253446	benign	Ataxia-telangiectasia-like disorder	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589610	SCV000698605	likely benign	not provided	2017-06-16	criteria provided, single submitter	clinical testing	Variant summary: The MRE11A c.1783+5G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict weakening effect on the canonical splicing donor site and ESEfinders predict change of ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 84/121382 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.007407 (77/10396). This frequency is about 119 times the estimated maximal expected allele frequency of a pathogenic MRE11A variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign until more evidence becomes available.
Athena Diagnostics Inc	RCV000589610	SCV000842792	benign	not provided	2019-01-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001287216	SCV001473883	uncertain significance	Ataxia-telangiectasia-like disorder 1	2020-02-14	criteria provided, single submitter	clinical testing	The MRE11 c.1783+5G>C variant (rs142082313), to our knowledge, is not reported in the medical literature but is reported as benign/likely benign in the ClinVar database (Variation ID: 127975). This variant is found in the African population with an allele frequency of 0.9% (224/24962 alleles, including 2 homozygotes) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, these predictions have not been confirmed by functional studies. Due to limited information, the clinical significance of this variant is uncertain at this time.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225331	SCV002504803	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115910	SCV002538406	likely benign	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477282	SCV002774026	benign	not specified	2021-07-20	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001287216	SCV004015927	benign	Ataxia-telangiectasia-like disorder 1	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935108	SCV004747537	benign	MRE11-related condition	2019-11-22	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).