Predictive functional assay-based classification of PMS2 variants in Lynch syndrome

Emily Rayner, Yvonne Tiersma, Cristina Fortuno, Sandrine van Hees-Stuivenberg, Mark Drost, Bryony Thompson, Amanda B. Spurdle, Niels de Wind*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch syndrome, represent variants of uncertain significance (VUS). The inability to classify most VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based quantitative tool to improve the classification of VUS in MMR proteins. To derive a formula that translates CIMRA assay results into the odds of pathogenicity (OddsPath) for VUS in PMS2 we used a set of clinically classified PMS2 variants supplemented by inactivating variants that were generated by an in cellulo genetic screen, as proxies for cancer-predisposing variants. Validation of this OddsPath revealed high predictive values for benign and predisposing PMS2 VUS. We conclude that the OddsPath provides an integral metric that, following the other, higher penetrance, MMR proteins MSH2, MSH6 and MLH1 can be incorporated as strong evidence type into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).

Original languageEnglish
Pages (from-to)1249-1258
Number of pages10
JournalHuman Mutation
Issue number9
Publication statusPublished - Sep 2022

Bibliographical note

This study was funded by the Dutch Cancer Society (Consortium grant 10645). Amanda B. Spurdle was supported by National Health and Medical Research Council (NHMRC, Australia) Fellowship funding (APP1061779 and APP1177524). Cristina Fortuno was supported by NHMRC project grant APP116589.

Publisher Copyright: © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.


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