ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.1480G>A (p.Glu494Lys)

gnomAD frequency: 0.00057  dbSNP: rs104895016
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Total submissions: 11
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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 2019-11-13 criteria provided, single submitter clinical testing The p.E494K variant (also known as c.1480G>A), located in coding exon 12 of the MRE11A gene, results from a G to A substitution at nucleotide position 1480. The glutamic acid at codon 494 is replaced by lysine, an amino acid with similar properties. In one study, this variant was seen at similar frequencies in patients with common variable immunodeficiency (CVID) or Immunoglobulin A deficiency (IgAD), and controls (Offer SM et al. PLoS One. 2010 Aug;5:e12260). In another study, which screened for variants in 17 breast cancer susceptibility genes, this variant was seen in 2/1824 patients with triple negative breast cancer, who were unselected for family history of breast and/or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 42 and had a family history of ovarian cancer (Caminsky NG et al. Hum. Mutat. 2016 Jul;37:640-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000791398 SCV000254852 likely benign Ataxia-telangiectasia-like disorder 2021-11-30 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000114896 SCV000614120 likely benign not provided 2020-07-15 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
CeGaT Center for Human Genetics Tuebingen RCV000114896 SCV001248580 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000524518 SCV001271757 uncertain significance 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV000114896 SCV001872700 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Couch 2015, Caminsky 2016); This variant is associated with the following publications: (PMID: 26898890, 25452441, 25344691)
Sema4,Sema4 RCV000131601 SCV002538395 likely benign Hereditary cancer-predisposing syndrome 2020-12-17 criteria provided, single submitter curation
Harris Lab, University of Minnesota RCV000114896 SCV000148791 not provided not provided no assertion provided not provided

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