Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.

Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium Max von Laue Str 15 60438 Frankfurt am Main Germany

Cell Death and Drug Resistance in Lymphoproliferative Disorders Team INSERM U1138 Centre de Recherche des Cordeliers Paris France

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Life Science Sorbonne Université Paris France

Department of Oncology Pathology Bioclinicum Karolinska Institutet Stockholm Sweden

Department of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

Equipe Labellisée par la Ligue Contre le Cancer Université Paris Descartes Université Sorbonne Paris Cité Université Paris Diderot Sorbonne Université INSERM U1138 Centre de Recherche des Cordeliers Paris France

Faculty of Science Department of Experimental Biology Masaryk University Brno Czech Republic

Institute of Pharmaceutical Chemistry Johann Wolfgang Goethe University Max von Laue Str 9 60438 Frankfurt am Main Germany

Metabolomics and Cell Biology Platforms Institut Gustave Roussy Villejuif France

Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France

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