ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.2092A>G (p.Met698Val)

gnomAD frequency: 0.00548  dbSNP: rs1805362
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128960 SCV000172841 benign Hereditary cancer-predisposing syndrome 2014-11-24 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign)
GeneDx RCV000117633 SCV000211162 benign not specified 2013-10-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001080129 SCV000261105 benign Ataxia-telangiectasia-like disorder 2021-12-11 criteria provided, single submitter clinical testing
Counsyl RCV000410760 SCV000488663 benign Ataxia-telangiectasia-like disorder 1 2016-06-08 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000712325 SCV000842794 benign not provided 2017-10-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000117633 SCV000919679 benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MRE11A c.2092A>G (p.Met698Val) results in a conservative amino acid change in the encoded protein sequence that is located outside of any known functional domains. 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 0.0019 in 270304 control chromosomes, predominantly within the African subpopulation at a frequency of 0.019, including 7 homozygotes in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 300 fold of 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. Moreover, the variant was found in 76/2559 African American women (with 1 homozygote), who are older than age 70 years, and who have never had cancer (in the FLOSSIES database). To our knowledge, 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 benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services,Illumina RCV000410760 SCV001268079 benign Ataxia-telangiectasia-like disorder 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000410760 SCV001471838 benign Ataxia-telangiectasia-like disorder 1 2020-05-28 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225341 SCV002504795 benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000117633 SCV000151865 likely benign not specified no assertion criteria provided clinical testing Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000117633 SCV001978383 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000117633 SCV001979975 benign not specified no assertion criteria provided clinical testing

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