Uncertain pathogenicity of MSH2 variants N127S and G322D challenges their classification

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 i...

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Bibliographic Details
Published in:International journal of cancer 2008-08, Vol.123 (3), p.720-724
Main Authors: Ollila, Saara, Bebek, Denis Dermadi, Greenblatt, Marc, Nyström, Minna
Format: Article
Language:English
Subjects:
Asparagine
Aspartic Acid
Biliary Tract Neoplasms - genetics
Biological and medical sciences
Blotting, Western
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
DNA Mismatch Repair
DNA-Binding Proteins - genetics
Endometrial Neoplasms - genetics
Female
functional analysis
Gastroenterology. Liver. Pancreas. Abdomen
Genetic Predisposition to Disease
Germ-Line Mutation
Glycine
hereditary non‐polyposis colorectal cancer
Humans
Immunoprecipitation
Medical sciences
mismatch repair
MSH2
MutS Homolog 2 Protein - genetics
Pancreatic Neoplasms - genetics
Serine
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
Uncertainty
unclassified variant
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Summary: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. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.23573