J.O. is a research fellow of the Third Department of Surgery, XinJiang Tumor Hospital, Xin Jiang Medical University, People's Republic of China.
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes†
Article first published online: 26 JUN 2007
© 2007 Wiley-Liss, Inc.
Volume 28, Issue 11, pages 1047–1054, November 2007
How to Cite
Ou, J., Niessen, R. C., Lützen, A., Sijmons, R. H., Kleibeuker, Jan. H., de Wind, N., Rasmussen, L. J. and Hofstra, R. M.W. (2007), Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum. Mutat., 28: 1047–1054. doi: 10.1002/humu.20580
Communicated by Georgia Chenevix-Trench
- Issue published online: 11 OCT 2007
- Article first published online: 26 JUN 2007
- Manuscript Revised: 19 MAY 2007
- Manuscript Accepted: 19 MAY 2007
- Manuscript Received: 31 JAN 2007
- Dutch Cancer Society. Grant Number: RUG2002-2678
- European Community. Grant Numbers: FP6-2004-LIFESCIHEALTH-5, Proposal 018754
- Lynch syndrome;
- mismatch repair genes;
- missense mutations;
- functional assays;
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is caused by DNA variations in the DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and PMS2. Many of the mutations identified result in premature termination of translation and thus in loss-of-function of the encoded mutated protein. These DNA variations are thought to be pathogenic mutations. However, some patients carry other DNA mutations, referred to as unclassified variants (UVs), which do not lead to such a premature termination of translation; it is not known whether these contribute to the disease phenotype or merely represent rare polymorphisms. This is a major problem which has direct clinical consequences. Several criteria can be used to classify these UVs, such as: whether they segregate with the disease within pedigrees, are absent in control individuals, show a change of amino acid polarity or size, provoke an amino acid change in a domain that is evolutionary conserved and/or shared between proteins belonging to the same protein family, or show altered function in an in vitro assay. In this review we discuss the various functional assays reported for the HNPCC-associated MMR proteins and the outcomes of these tests on UVs identified in patients diagnosed with or suspected of having HNPCC. We conclude that a large proportion of MMR UVs are likely to be pathogenic, suggesting that missense variants of MMR proteins do indeed play a role in HNPCC. Hum Mutat 28(11), 1047–1054, 2007. © 2007 Wiley-Liss, Inc.