title: Truncation of the MSH2 C-terminal 60 amino acids disrupts effective DNA mismatch repair and is causative for Lynch syndrome.
abstract: Missense variants of DNA mismatch repair (MMR) genes pose a problem in clinical genetics as long as they cannot unambiguously be assigned as the cause of Lynch syndrome (LS). To study such variants of uncertain clinical significance, we have developed a functional assay based on direct measurement of MMR activity in mouse embryonic stem cells expressing mutant protein from the endogenous alleles. We have applied this protocol to a specific truncation mutant of MSH2 that removes 60 C-terminal amino acids and has been found in suspected LS families. We show that the stability of the MSH2/MSH6 heterodimer is severely perturbed, causing attenuated MMR in in vitro assays and cancer predisposition in mice. This mutation can therefore unambiguously be considered as deleterious and causative for LS.
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Wielders
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Elly
authors.initials: E
authors.lastname: Delzenne-Goette
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Dekker
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: van der Valk
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. h.t.riele@nki.nl.
authors.forename: Hein
authors.identifier: 0000-0003-0255-4042
authors.initials: H
authors.lastname: Te Riele
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense
chemical_list: D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein
keywords: DNA mismatch repair; Lynch syndrome; MSH2; VUS; Variants of uncertain clinical significance