Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis.

Area of Science:

• Genetics
• Oncology
• Population Studies

Background:

• Variable cancer penetrance in Li-Fraumeni syndrome (LFS) necessitates a re-evaluation of pathogenic germline TP53 variant prevalence.
• Previous studies indicated higher-than-expected population prevalence of TP53 variants in cancer-unselected sequencing databases.

Purpose of the Study:

• To assess the prevalence of pathogenic and likely pathogenic germline TP53 variants within the gnomAD dataset (v2.0.2, n=138,632).
• To compare prevalence estimates derived from a validated algorithm with those from ClinVar, HGMD, and UMD_TP53 databases.

Main Methods:

• Germline TP53 variants were identified and classified using a previously established algorithm within the gnomAD dataset.
• Variant classifications were cross-referenced with ClinVar, HGMD, and UMD_TP53 databases for comparative analysis.
• Prevalence estimates were calculated using both conservative and less stringent variant classification criteria.

Main Results:

• Conservative estimates indicate a prevalence of 1 pathogenic/likely pathogenic TP53 variant carrier in 3,555-5,476 individuals.
• Less stringent classification, including controversial variants (p.N235S, p.V31I, p.R290H), increased prevalence to 1 in 400-865 individuals.
• The study confirms a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants.

Conclusions:

• Population prevalence of pathogenic and likely pathogenic germline TP53 variants is higher than previously assumed, even with conservative estimates.
• Current prevalence estimates may not directly correlate with the classical Li-Fraumeni syndrome phenotype, which relies on family cancer history.
• Further research integrating variant classification, prevalence data, cancer penetrance, and LFS phenotype is crucial for comprehensive understanding.