title: Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors.
abstract: Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: M
authors: M
authors: Pineda
authors: M
authors: M
authors: González-Acosta
authors: B A
authors: BA
authors: Thompson
authors: R
authors: R
authors: Sánchez
authors: C
authors: C
authors: Gómez
authors: J
authors: J
authors: Martínez-López
authors: J
authors: J
authors: Perea
authors: T
authors: T
authors: Caldés
authors: Y
authors: Y
authors: Rodríguez
authors: S
authors: S
authors: Landolfi
authors: J
authors: J
authors: Balmaña
authors: C
authors: C
authors: Lázaro
authors: L
authors: L
authors: Robles
authors: G
authors: G
authors: Capellá
authors: D
authors: D
authors: Rueda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D001665:Binding Sites; D003062:Codon; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D005190:Family; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003062:Codon; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1
keywords: HNPCC; Lynch syndrome; MLH1; variants of unknown significance