Urgent need to recognize that disease-causing TP53 variants with atypical penetrance require distinct clinical recommendations

TP53 germline pathogenic variants are among the most significant genetic causes of cancer across all age groups. Current TP53 variant classification guidelines are designed to identify high penetrance TP53 variants that lead to a phenotype called Li-Fraumeni syndrome. However, they are insufficient to accurately classify variants conferring atypical penetrance. These atypical penetrance variants are disease-causing, but the phenotype is often attenuated. Using current TP53 variant classification guidelines, atypical penetrance variants are not properly recognized leading to sub-optimal management of individuals carrying such variants. We highlight the need to develop strategies to consistently identify atypical penetrance disease-causing germline TP53 variants including development of variant classification specifications tailored to distinguish such variants, and to define the associated cancer spectrum and age-related risks. These studies will inform modifications to the existing standard risk management recommendations.