title: Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome.
abstract: 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.
authors: Department of Cancer Genetics, Mater Private Hospital, Dublin 7, Ireland. farrelm7@tcd.ie
authors: Michael P
authors: MP
authors: Farrell
authors: David J
authors: DJ
authors: Hughes
authors: Ian R
authors: IR
authors: Berry
authors: David J
authors: DJ
authors: Gallagher
authors: Emily A
authors: EA
authors: Glogowski
authors: Stewart J
authors: SJ
authors: Payne
authors: Michael J
authors: MJ
authors: Kennedy
authors: Róisín M
authors: RM
authors: Clarke
authors: Susan A
authors: SA
authors: White
authors: Cian B
authors: CB
authors: Muldoon
authors: Fiona
authors: F
authors: Macdonald
authors: Pauline
authors: P
authors: Rehal
authors: Danielle
authors: D
authors: Crompton
authors: Solvig
authors: S
authors: Roring
authors: Sarah T
authors: ST
authors: Duke
authors: Trudi
authors: T
authors: McDevitt
authors: David E
authors: DE
authors: Barton
authors: Shirley V
authors: SV
authors: Hodgson
authors: Andrew J
authors: AJ
authors: Green
authors: Peter A
authors: PA
authors: Daly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1