ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.274G>A (p.Glu92Lys) (rs587780139)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656866 SCV000149824 uncertain significance not provided 2014-03-13 criteria provided, single submitter clinical testing MRE11A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted MRE11A c.274G>A at the cDNA level, p.Glu92Lys (E92K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Glu92Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a negative polar amino acid is replaced with a positive polar one, altering a position that is moderately conserved throughout evolution and is located in the phosphodiesterase and Nuclease I-V domains (Bartkova 2008, Stracker 2011). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a 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. Furthermore, based on the currently available information, cancer risks associated with this variant, and the MRE11A gene, remain unclear.
Ambry Genetics RCV000115915 SCV000214555 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000791353 SCV000547427 uncertain significance Ataxia-telangiectasia-like disorder 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 92 of the MRE11 protein (p.Glu92Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MRE11-related disease. ClinVar contains an entry for this variant (Variation ID: 127980). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000212555 SCV000614124 uncertain significance not specified 2017-06-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000684785 SCV000894683 uncertain significance Ataxia-telangiectasia-like disorder 1 2018-10-31 criteria provided, single submitter clinical testing

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