Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome
Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.
KeywordsImmunohistochemical analysis Lynch syndrome Microsatellite instability Mismatch repair Muir-Torre syndrome Mutl homolog 1 Variant of uncertain significance
The authors wish to sincerely thank the members of the families described, Dr. Eric Rosenthal at Myriad Genetics Laboratories and to acknowledge the contribution of Wilma Ormiston, T.J. Boyle, C.H. Nolan, B.J. Mehigan, R.B. Stephens, D. Flannery of St. James’s Hospital, Stephen G. Smith of the Department of Microbiology TCD, Steven G. Gray and Kathy A. Gately of the Translational Research Group, TCD, Paul. C. Smyth and Orla M. Sheils of the Dept. of Histopathology TCD, Michael O. Woods and Amanda Dohey of Memorial University of Newfoundland, Canada, Dr. Qing Wang, Unité d’Oncologie Moléculaire, Centre Léon Bérard, Lyon, France, Peter J. Holdsworth of the Dept. of General Surgery, Huddersfield Royal Infirmary, U.K, Dr. Julian W. Adlard of the Dept. of Clinical Genetics, Yorkshire Regional Genetic Service, Leeds, U.K, Nils Rahner and Verena Steinke of University of Bonn, Institute of Human Genetics, Germany, Pascale Hilbert of Institut de Pathologie et de Génétique, Département de Biologie Moléculaire, Gosselies, Belgium, Professor Gareth Evans of St. Mary’s Hospital, Manchester, U.K.
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