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. 2020 Jan;41(1):203-211.
doi: 10.1002/humu.23910. Epub 2019 Sep 23.

A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically

Bradford Coffee  1 , Hannah C Cox  1 , Ryan Bernhisel  1 , Susan Manley  1 , Karla Bowles  1 , Benjamin B Roa  1 , Debora Mancini-DiNardo  1
Affiliations

A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically

Bradford Coffee et al. Hum Mutat. 2020 Jan.

Abstract

Previous analysis of next-generation sequencing (NGS) hereditary pan-cancer panel testing demonstrated that approximately 40% of TP53 pathogenic and likely pathogenic variants (PVs) detected have NGS allele frequencies between 10% and 30%, indicating that they likely are acquired somatically. These are seen more frequently in older adults, suggesting that most result from normal aging-related clonal hematopoiesis. For this analysis, apparent heterozygous germline TP53 PV carriers (NGS allele frequency 30-70%) were offered follow-up testing to confirm variant origin. Ninety-eight probands had samples submitted for follow-up family member testing, fibroblast testing, or both. The apparent heterozygous germline TP53 PV was not detected in 32.6% (15/46) of submitted fibroblast samples, indicating that it was acquired somatically, either through clonal hematopoiesis or via constitutional mosaicism. Notably, no individuals with confirmed germline or likely germline TP53 PVs met classic Li-Fraumeni syndrome (LFS) criteria, only 41% met Chompret LFS criteria, and 59% met neither criteria, based upon provider-reported personal and family cancer history. Comprehensive reporting of TP53 PVs detected using NGS, combined with follow-up analysis to confirm variant origin, is advised for clinical testing laboratories. These findings underscore the investment required to provide individuals and family members with clinically accurate genetic test results pertaining to their LFS risk.

Keywords: Li-Fraumeni syndrome; TP53; acquired somatically; hereditary pan-cancer gene panel; next-generation sequencing; pathogenic variant.

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Conflict of interest statement

All authors are employed by Myriad Genetic Laboratories, Inc. and receive salaries as compensation.

Figures

Figure 1
Figure 1
Follow‐up testing schema. The possible interpretations of follow‐up test results are provided for family testing and fibroblast testing in the proband
Figure 2
Figure 2
(a) Age at diagnosis and (b) age at testing for individuals with an apparent germline TP53 PV identified by hereditary cancer genetic testing. Results are stratified according to the results of follow‐up testing
Figure 3
Figure 3
Allele frequencies for (a) somatic TP53 PVs (N = 15) and (b) confirmed germline (N = 19) and likely germline (N = 37) TP53 PVs. Only sequence variants are included. NGS, next‐generation sequencing; PV, pathogenic variant
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