Work

Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification

Year: 2008

Type: article

Abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with germline mutations in mismatch repair (MMR) genes. Inherited missense mutations, however, complicate the diagnostics because they do not always cause unambiguous predisposition to cancer. This leads to variable and contradictory interpretations of their pathogenicity. Here, we establish evidence for the functionality of the 2 frequently reported variations, MSH2 N127S and G322D, which have been described both as pathogenic and non-pathogenic in literature and databases. We report the results of 3 different functional analyses characterizing the biochemical properties of these protein variants in vitro. We applied an immunoprecipitation assay to assess the MSH2-MSH6 interaction, a bandshift assay to study mismatch recognition and binding, and a MMR assay for repair efficiency. None of the experiments provided evidence on reduced functionality of these proteins as compared to wild-type MSH2. Our data demonstrate that MSH2 N127S and G322D per se are not sufficient to trigger MMR deficiency. This together with variable clinical phenotypes in the mutation carriers suggest no or only low cancer risk in vivo.

Source: International Journal of Cancer

DOI: 10.1002/ijc.23573

Authors: Saara Ollila, Denis Dermadi Bebek, Marc Greenblatt, Minna Nyström

Institutions: University of Helsinki, University of Vermont

Language: English

Topic: Genetic factors in colorectal cancer

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Academy of Finland, National Institutes of Health, National Cancer Institute