title: Co-occurrence of nonsense mutations in MSH6 and MSH2 in Lynch syndrome families evidencing that not all truncating mutations are equal.
abstract: The majority of pathogenic mismatch repair (MMR) gene mutations detected in Lynch syndrome patients are truncating (frameshift or nonsense). However, the classification of terminal truncating mutations is sometimes difficult and predictive testing based on non-deleterious variants can have very serious consequences. Here, we report eight probands that have two germline nonsense mutations, namely MSH6 c.1030C>T, p.(Gln344Ter) and MSH2 c.2785C>T, p.(Arg929Ter), and one additional patient who presented only the MSH2 mutation previously reported as deleterious. The novel MSH6 truncating mutation was classified as deleterious, as it is predicted to encode a protein with loss of 1017 amino acid residues. The MSH2 mutation, which is expected to encode a protein lacking six amino acid residues, was considered a variant of unknown significance. Five tumors of the eight double-mutant individuals had normal MSH2 expression, whereas MSH6 immunoexpression was lost in all evaluable cases. None of the variants were detected in normal controls or associated with other MMR germline mutations in our series. This study emphasizes that not all truncating mutations are equal and that one must be cautious in the interpretation of the presumed deleterious effect of terminal frameshift or nonsense mutations.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Peixoto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Santos
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Rocha
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Department of Pathology, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Lopes
authors.affiliation: Department of Surgery, São João Hospital, Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Baptista
authors.affiliation: Department of Pathology, Portuguese Oncology Institute, Porto, Portugal.|Institute of Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.|Institute of Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D018389:Codon, Nonsense; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005190:Family; D006239:Haplotypes; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein