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. 2024 Jan 11;5(1):100242.
doi: 10.1016/j.xhgg.2023.100242. Epub 2023 Sep 29.

Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants

Kelvin C de Andrade  1 , Natasha T Strande  2 , Jung Kim  3 , Jeremy S Haley  2 , Jessica N Hatton  3 , Megan N Frone  3 , Payal P Khincha  3 , Gretchen M Thone  2 , Uyenlinh L Mirshahi  2 , Cynthia Schneider  4 , Heena Desai  4 , James T Dove  2 , Diane T Smelser  2 ; Penn Medicine BioBank; Regeneron Genetics Center; Arnold J Levine  5 , Kara N Maxwell  4 , Douglas R Stewart  3 , David J Carey  2 , Sharon A Savage  3
Affiliations

Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants

Kelvin C de Andrade et al. HGG Adv. .

Abstract

Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants was conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB. These estimates were calculated after excluding related individuals and accounting for the potential impact of clonal hematopoiesis by excluding heterozygotes who ever developed a hematologic cancer. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance.

Keywords: Geisinger; LFS; Li-Fraumeni syndrome; Penn Medicine; TP53; UK Biobank; cancer genetics; cancer risk; genome-first; inherited cancer.

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Conflict of interest statement

Declaration of interests K.C.A., J.N.H., M.N.F., and S.A.S. are unpaid members of the ClinGen TP53 Variant Curation Expert Panel. M.N.F. is a co-developer of CancerGene Connect. A.J.L. is a director of PMV Pharma.

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