ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.1475C>A (p.Ala492Asp) (rs61749249)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114897 SCV000149816 uncertain significance not provided 2014-03-06 criteria provided, single submitter clinical testing The MRE11A gene has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.1475C>A at the cDNA level, p.Ala492Asp (A492D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant has not, to our knowledge, been reported as a pathogenic variant or a benign polymorphism. It was observed in the NHLBI Exome Sequencing Project with an allele frequency of 0.6% (54/8596) in European Americans and 0.2% (7/4402) in African Americans, not frequent enough to be considered a polymorphism. MRE11A Ala492Asp is a non-conservative substitution of a neutral non-polar amino acid for a negative polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. At the molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance.
Ambry Genetics RCV000115907 SCV000172746 benign Hereditary cancer-predisposing syndrome 2014-08-07 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Genetic Services Laboratory,University of Chicago RCV000193395 SCV000248073 uncertain significance not specified 2014-06-27 criteria provided, single submitter clinical testing
Invitae RCV001079570 SCV000253443 benign Ataxia-telangiectasia-like disorder 2019-12-29 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000193395 SCV000341540 likely benign not specified 2016-04-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000524517 SCV000604243 uncertain significance Ataxia-telangiectasia-like disorder 1 2019-02-28 criteria provided, single submitter clinical testing The p.Ala492Asp variant (rs61749249) has not been reported in the medical literature, gene specific variation databases, but it has been reported to ClinVar (Variation ID: 127031). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.34 percent (identified on 932 out of 277,128 chromosomes, including 3 homozygotes). The alanine at position 492 is moderately conserved (Alamut v2.9.0) and computational analyses of the effects of the p.Ala492Asp variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ala492Asp variant with certainty.
Counsyl RCV000524517 SCV000785308 likely benign Ataxia-telangiectasia-like disorder 1 2017-07-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000114897 SCV000842789 likely benign not provided 2018-08-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000114897 SCV001148387 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000524517 SCV001271758 benign Ataxia-telangiectasia-like disorder 1 2017-04-27 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.
Harris Lab, University of Minnesota RCV000114897 SCV000148792 not provided not provided no assertion provided not provided

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