Submissions for variant NM_005591.4(MRE11):c.1798G>C (p.Glu600Gln)

gnomAD frequency: 0.00103  dbSNP: rs145415033

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131661	SCV000186688	likely benign	Hereditary cancer-predisposing syndrome	2018-12-10	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	RCV001081514	SCV000253447	likely benign	Ataxia-telangiectasia-like disorder	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731881	SCV000859749	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781549	SCV000919682	benign	not specified	2018-10-29	criteria provided, single submitter	clinical testing	Variant summary: MRE11A c.1798G>C (p.Glu600Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 276710 control chromosomes (including 1 homozygote), predominantly within the African subpopulation with a frequency of 0.003 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 50 fold above the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. In addition, the variant was reported in 21/2559 African American women (i.e. with a frequency of 0.0082), who were older than 70 years of age, and never had cancer (in the FLOSSIES database). To our knowledge, no occurrence of c.1798G>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001112603	SCV001270279	uncertain significance	Ataxia-telangiectasia-like disorder 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225446	SCV002504802	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131661	SCV002538408	likely benign	Hereditary cancer-predisposing syndrome	2022-01-30	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001112603	SCV004015921	likely benign	Ataxia-telangiectasia-like disorder 1	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000731881	SCV004220918	likely benign	not provided	2019-09-06	criteria provided, single submitter	clinical testing