ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.1480G>A (p.Glu494Lys) (rs104895016)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131601 SCV000186616 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Athena Diagnostics Inc RCV000114896 SCV000614120 uncertain significance not provided 2017-12-30 criteria provided, single submitter clinical testing
Counsyl RCV000524518 SCV000785843 uncertain significance Ataxia-telangiectasia-like disorder 1 2017-12-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000524518 SCV000896213 uncertain significance Ataxia-telangiectasia-like disorder 1 2018-10-31 criteria provided, single submitter clinical testing
Harris Lab, University of Minnesota RCV000114896 SCV000148791 not provided not provided no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000781546 SCV000919675 benign not specified 2018-02-16 criteria provided, single submitter clinical testing Variant summary: MRE11A c.1480G>A (p.Glu494Lys) results in a conservative amino acid change located in the outside of any known domain or repeat of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency of 0.00049 (136/277134 chrs) is approximately 8.083 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 benign. The c.1480G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000791398 SCV000254852 uncertain significance Ataxia-telangiectasia-like disorder 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 494 of the MRE11 protein (p.Glu494Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs104895016, ExAC 0.09%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25452441, 26898890). ClinVar contains an entry for this variant (Variation ID: 127030). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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