Analysis of Role of Different Genetic Variants Involved in Lynch Syndrome

An international study allows a better prediction of the risk of hereditary cancer, a critical component for genetic counselling

An international study has developed a refined method to identify people at risk for certain inherited cancers as a result of Lynch syndrome. The study, published in Nature Genetics have been performed by clinicians and researchers who are part of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) and analysed the role of different genetic variants involved in Lynch syndrome.

Lynch syndrome is an inherited disease that increases the risk of various tumours, especially colon and endometrial cancers, being responsible for between 2 and 5% of cases. Research published in Nature Genetics has focused on studying the genetic causes of Lynch syndrome. Often the result of the genetic study of patients with this syndrome is not informative, since relevance of genetic variants is unknown: one can not predict their biological significance and clinical implications. It is therefore unknown whether these patients have a higher risk of developing other cancers, or if their family members are also at risk.

The research team undertook a collaborative effort to develop, test and apply a standardised classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2.

The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online.
Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature.

This cooperative effort demonstrates the value of multidisciplinary collaboration in the classification of variants in public locus-specific databases. It classifies a large number of variants of unknown significance. The classification of a variant responsible for Lynch syndrome is critical for genetic counselling of families suspected to have the syndrome and allows predictive study of families at risk. If they are carriers, it can help them to take preventive measures and adequate monitoring.


Thompson BA, Spurdle AB, Plazzer JP, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2013 December 22. doi: 10.1038/ng.2854. [Epub ahead of print].