Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene

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 ger...

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Bibliographic Details
Published in:	Cell death and differentiation Vol. 28; no. 5; pp. 1477 - 1492
Main Authors:	Doffe, Flora, Carbonnier, Vincent, Tissier, Manon, Leroy, Bernard, Martins, Isabelle, Mattsson, Johanna S. M., Micke, Patrick, Pavlova, Sarka, Pospisilova, Sarka, Smardova, Jana, Joerger, Andreas C., Wiman, Klas G., Kroemer, Guido, Soussi, Thierry
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-05-2021 Nature Publishing Group
Subjects:	13/31 13/44 45/70 631/67/1244 692/308/2056 82/80 96/109 Apoptosis Biochemistry Biomedical and Life Sciences Cancer Cell Biology Cell Cycle Analysis Datasets Disease Genes, p53 - genetics Genetic analysis Genetic diversity Genetics Genomes Genomics Humans Identification Immunology Leukemia Life Sciences Medicin och hälsovetenskap Multiculturalism & pluralism Mutation Mutation, Missense - genetics Neoplasms - genetics p53 Protein Pathology Patologi Polymorphism Polymorphism, Single Nucleotide - genetics Population Single-nucleotide polymorphism Stem Cells Structure-function relationships Tumor Suppressor Protein p53 - genetics Tumors
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1350-9047 1476-5403 1476-5403
DOI:	10.1038/s41418-020-00672-0