ClinVar Miner

Submissions for variant NM_005591.4(MRE11):c.1726C>G (p.Arg576Gly)

gnomAD frequency: 0.00016  dbSNP: rs774277300
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166359 SCV000217147 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-01 criteria provided, single submitter clinical testing The p.R576G variant (also known as c.1726C>G), located in coding exon 14 of the MRE11A gene, results from a C to G substitution at nucleotide position 1726. The arginine at codon 576 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000524520 SCV000547399 uncertain significance Ataxia-telangiectasia-like disorder 2025-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 576 of the MRE11 protein (p.Arg576Gly). This variant is present in population databases (rs774277300, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MRE11-related conditions. ClinVar contains an entry for this variant (Variation ID: 186717). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000505885 SCV000604242 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252012 SCV002523258 uncertain significance See cases 2019-09-26 criteria provided, single submitter clinical testing ACMG classification criteria: PM2
Sema4, Sema4 RCV000166359 SCV002538401 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-04 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505885 SCV002570789 uncertain significance not specified 2022-07-11 criteria provided, single submitter clinical testing Variant summary: MRE11 (also known as MRE11A) c.1726C>G (p.Arg576Gly) 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 4e-05 in 251314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MRE11 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1726C>G has been reported in the literature in individuals affected with colorectal cancer. This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 uncertain significance.
PreventionGenetics, part of Exact Sciences RCV003407619 SCV004107846 uncertain significance MRE11-related disorder 2022-10-19 criteria provided, single submitter clinical testing The MRE11 c.1726C>G variant is predicted to result in the amino acid substitution p.Arg576Gly. This variant has been reported with uncertain significance in a study of individuals of Asian descent with young-onset colorectal cancer (Supplemental Results, Toh et al. 2018. PubMed ID: 31360874). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-94180442-G-C) and is reported with uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186717/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV003468781 SCV004193871 uncertain significance Ataxia-telangiectasia-like disorder 1 2023-02-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477628 SCV004220916 uncertain significance not provided 2023-12-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV003468781 SCV005631427 uncertain significance Ataxia-telangiectasia-like disorder 1 2024-02-21 criteria provided, single submitter clinical testing

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