ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.1811G>C (p.Arg604Pro) (rs148637964)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656869 SCV000149821 uncertain significance not provided 2013-10-29 criteria provided, single submitter clinical testing MRE11A, which is involved in DNA damage repair, has been only recently described in association with cancer predisposition and the risks are not well understood.This variant is denoted MRE11A c.1811G>C at the cDNA level, p.Arg604Pro (R604P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MRE11A Arg604Pro was observed at an allele frequency of 0.1% in 1000 Genomes (0.4% among individuals of African ancestry.) This variant is a non-conservative amino acid substitution, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect 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 RCV000115912 SCV000183828 likely benign Hereditary cancer-predisposing syndrome 2017-07-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Invitae RCV000524525 SCV000259440 uncertain significance Ataxia-telangiectasia-like disorder 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 604 of the MRE11 protein (p.Arg604Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs148637964, ExAC 0.2%). This variant has not been reported in the literature in individuals with an MRE11-related disease. ClinVar contains an entry for this variant (Variation ID: 127977). 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 C0"). In summary, this variant has uncertain impact on MRE11 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212571 SCV000604244 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212571 SCV000919680 uncertain significance not specified 2018-08-27 criteria provided, single submitter clinical testing Variant summary: MRE11A c.1811G>C (p.Arg604Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 276718 control chromosomes. The observed variant frequency is approximately 3.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), suggesting that the variant is benign. However, due to potential pseudogen interference, this data must be interpreted with caution. To our knowledge, no occurrence of c.1811G>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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