Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome

Genetics in Medicine, vol. 22, pp. 847–856

Abstract

PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

Authors 16

1. Mark Drost Aachen Department of Human Genetics

   Leiden University Medical Center · Erasmus MC

   Affiliation as printed

   Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

2. Yvonne Tiersma Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

3. Dylan M. Glubb

   QIMR Berghofer Medical Research Institute

   Affiliation as printed

   Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia

4. Scott D. Kathe

   University of Vermont

   Affiliation as printed

   Departments of Microbiology and Molecular Genetics and Medicine, University of Vermont Cancer Center, University of Vermont Robert Larner College of Medicine, Burlington, VT, USA

5. Sandrine van Hees Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

6. Fabienne M.G.R. Calléja Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

7. José B.M. Zonneveld Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

8. Kenneth M. Boucher

   University of Utah · Huntsman Cancer Institute

   Affiliation as printed

   Department of Medicine, Division of Epidemiology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

9. Renuka P. E. Ramlal Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

10. Bryony A. Thompson

    The University of Melbourne · University of Utah · Huntsman Cancer Institute

    Affiliation as printed

    Department of Clinical Pathology, University of Melbourne, Melbourne, Australia

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

11. Lene Juel Rasmussen

    University of Copenhagen

    Affiliation as printed

    Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

12. Marc S. Greenblatt

    University of Vermont

    Affiliation as printed

    Departments of Microbiology and Molecular Genetics and Medicine, University of Vermont Cancer Center, University of Vermont Robert Larner College of Medicine, Burlington, VT, USA

13. Andrea Lee

    University of Vermont

    Affiliation as printed

    Departments of Microbiology and Molecular Genetics and Medicine, University of Vermont Cancer Center, University of Vermont Robert Larner College of Medicine, Burlington, VT, USA

14. Amanda B. Spurdle

    QIMR Berghofer Medical Research Institute

    Affiliation as printed

    Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia

15. Sean V. Tavtigian corresponding

    University of Utah · Huntsman Cancer Institute

    Affiliation as printed

    Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

16. Niels de Wind corresponding Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. N.de_Wind@lumc.nl

    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands