ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.391G>A (p.Asp131Asn) (rs368403414)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130877 SCV000185782 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000642460 SCV000764141 uncertain significance Ataxia-telangiectasia-like disorder 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 131 of the MRE11 protein (p.Asp131Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs368403414, ExAC 0.01%). This variant has been reported in the literature in individuals affected with familial breast and/or ovarian cancer (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 142063). 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: "Possibly Damaging"; 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.
Integrated Genetics/Laboratory Corporation of America RCV000781547 SCV000919676 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: MRE11A c.391G>A (p.Asp131Asn) results in a conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 275990 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer (4.7e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.391G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These reports do not provide unequivocal conclusions about an association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000994699 SCV001148391 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing

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