UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families

P Grandval,S Baert-Desurmont,A J Fabre,Q Wang,M.-P Buisine,P Gaildrat,S Olschwang,C Beroud,A Ferrari

doi:10.1093/database/bat036

Abstract

Lynch syndrome is an autosomal dominant disease caused by germ line heterozygous mutations mainly involving the MSH2, MLH1 and MSH6 genes that belong to the DNA MisMatch Repair (MMR) genes family. The French network counting the 16 licensed laboratories involved in Lynch syndrome genetic testing developed three locus-specific databases with the UMD® software (www.umd.be/MLH1/, www.umd.be/MSH2/ and www.umd.be/MSH6/) that presently contain a total of 7047 sequence variations including 707 distinct variations of a priori unknown functional significance (VUS) that were identified through complete mutation screening or targeted predictive testing. Mutation carriers are at high risk for developing early-onset colorectal and endometrial adenocarcinomas. Consensus clinical guidelines have been proposed, allowing the efficient detection of curable lesions. The major challenge of genetic testing is to reliably classify the genomic variations in those patients who seek genetic counseling. Combining the interactive tools of the software, the relevant published data and mainly original information produced by the French MisMatch Repair network, the UMD-MLH1/MSH2/MSH6 databases provide interpretation data for the 707 VUS that were classified according to the IARC 5-Class system. These public databases are regularly updated to improve the classification of all registered VUS, exploring their role in cancer pre-disposition based on structural and functional approaches.

Highlights

Mismatch repair (MMR) genes mutation carriers are a subgroup of colorectal cancer prone individuals who, when identified, benefit from highly effective risk management [1]
UMD-MLH1/MSH2/MSH6 databases In June 2012, the 16 licensed laboratories belonging to the French MisMatch Repair (MMR) network reported 2562 variations for MLH1, 2731 for MSH2 and 1754 for MSH6
They represent 429 different variations on MLH1, 455 on MSH2 and 290 on MSH6. These different variations were predicted to result in protein truncation in 171 (40%) occasions on MLH1, 199 (44%) on MSH2 and 97 (33%) on MSH6

Summary

Introduction

Mismatch repair (MMR) genes mutation carriers are a subgroup of colorectal cancer prone individuals who, when identified, benefit from highly effective risk management [1]. The genetic condition, Lynch syndrome, shows autosomal dominant inheritance and incomplete penetrance. This condition is genetically heterogeneous, as at least four MMR genes (MSH2, MLH1, MSH6 and PMS2) are implicated. Most of the causative mutations have been identified in two of them, MSH2 and MLH1. Monitoring of microsatellite DNA instability (MSI) in tumor cells provides good sensitivity but much lower specificity for the diagnosis of the syndrome.

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