A substantial proportion of apparently heterozygousTP53pathogenic variants detected with a next‐generation sequencing hereditary pan‐cancer panel are acquired somatically

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.

Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines

“…As noted above and in Table 4, the utility of HER2+ breast tumor phenotype for classification of TP53 variants identified in women diagnosed ≥40 years is currently unclear, and the higher rate of likely somatic variants in blood in older age groups (Coffee et al, 2017; Weitzel et al, 2017) make analyses more challenging. We excluded individuals with known or suspected somatic TP53 variants from our analysis datasets but acknowledge that unrecognized somatic variants may be present (Coffee et al, 2020; Mester et al, 2020). However, based on the report of median age at diagnosis of 44 years for individuals with confirmed somatic TP53 variants (Coffee et al, 2020), we believe that this phenomenon is unlikely to have confounded our LR estimates for women aged under 40 years.…”

“…We excluded individuals with known or suspected somatic TP53 variants from our analysis datasets but acknowledge that unrecognized somatic variants may be present (Coffee et al, 2020; Mester et al, 2020). However, based on the report of median age at diagnosis of 44 years for individuals with confirmed somatic TP53 variants (Coffee et al, 2020), we believe that this phenomenon is unlikely to have confounded our LR estimates for women aged under 40 years.…”

“…However, based on the report of median age at diagnosis of 44 years for individuals with confirmed somatic TP53 variants (Coffee et al, 2020), we believe that this phenomenon is unlikely to have confounded our LR estimates for women aged under 40 years.…”

“…As noted above and in Table 4, the utility of HER2+ breast tumor phenotype for classification of TP53 variants identified in women diagnosed ≥40 years is currently unclear, and the higher rate of likely somatic variants in blood in older age groups (Coffee et al, 2017;Weitzel et al, 2017) make analyses more challenging. We excluded individuals with known or suspected somatic TP53 variants from our analysis datasets but acknowledge that unrecognized somatic variants may be present (Coffee et al, 2020;Mester et al, 2020).…”

Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

“…Several studies pointed out that low allele frequencies (<25–35%) in blood from older patients might result from aberrant clonal expansion (ACE) events, mostly due to age- or therapy-related clonal hematopoiesis of indeterminate potential (CHIP) [ 5 , 6 , 7 , 8 , 9 ]. In the study from Weitzel and colleagues on 1454 adult patients tested with multigene panels including TP53 , about 20% of the positive patients showed a low allele frequency, most of whom had the mutation confined to the blood [ 6 ].…”