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Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification by Saara Ollila; Denis Dermadi Bebek; Marc Greenblatt; Minna Nyström is a Medicine article available to read on EtoBox.

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## 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 can

Who reads Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification?

Author

Saara Ollila; Denis Dermadi Bebek; Marc Greenblatt; Minna Nyström

Publisher

John Wiley and Sons; Wiley (John Wiley & Sons); John Wiley & Sons Inc.; Wiley; Research Square; Test accounts (ISSN 0020-7136)

Published

2008

Language

EN

Field

Medicine (Health Sciences)