Predictive functional assay‐based classification of PMS2 variants in Lynch syndrome
Human Mutation, vol. 43, pp. 1249–1258
Abstract
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).
Authors 8
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Emily Rayner Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Human Genetics
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics Leiden University Medical Center Leiden the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Yvonne Tiersma Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Human Genetics
Leiden University Medical Center · Princess Máxima Center
Affiliation as printed
Department of Human Genetics Leiden University Medical Center Leiden the Netherlands
Princess Maxima Center for Child Oncology Utrecht the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Princess Maxima Center for Child Oncology, Utrecht, the Netherlands
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QIMR Berghofer Medical Research Institute
Affiliation as printed
QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
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Sandrine van Hees‐Stuivenberg Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Human Genetics
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics Leiden University Medical Center Leiden the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Mark Drost Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands 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
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Department of Pathology Royal Melbourne Hospital Parkville Victoria Australia
Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia
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QIMR Berghofer Medical Research Institute
Affiliation as printed
QIMR Berghofer Medical Research Institute Brisbane Queensland Australia
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
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Niels de Wind corresponding Aachen Department of Human Genetics Leiden University Medical Center Leiden The Netherlands Department of Human Genetics
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics Leiden University Medical Center Leiden the Netherlands
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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