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The increasing use of multigene panel tests may reveal an unexpected pathogenic variant in the tumor protein p53 (TP53) gene among individuals who do not meet clinical criteria for Li-Fraumeni syndrome (LFS). Among a registry-based sample of individuals with a pathogenic (P) or likely pathogenic (LP) variant in TP53, we sought to characterize the original clinical context in which genetic testing was performed, the personal and family history and whether they met clinical LFS criteria, and the follow-up care following diagnosis among those in whom this information was available.Among individuals with multigene panel testing (inclusive of the TP53 gene) who were part of either the Inherited Cancer Registry or the Vanderbilt Hereditary Cancer Registry protocols and were confirmed to have a P/LP variant in TP53, pedigree was reviewed to characterize personal and family history, including original clinical context for genetic testing and whether they met clinical diagnostic criteria for TP53. Subsequent cancer risk management options were documented through information collected in the study questionnaire and medical records.Among the 10 participants enrolled in one of the two registries with a germline TP53 P/LP variant detected through a multigene panel test, the most frequent clinical contexts for testing were genetic risk recognized in the survivorship care setting (50%) and a newly diagnosed breast cancer (40%). No participants met classic LFS diagnostic criteria and 6 of 10 met Chompret criteria (60%) at the time of testing. Among the seven participants in whom results of total body magnetic resonance imaging were available, only three had completely negative findings. The remaining four had findings, three of which were likely benign/incidental requiring additional follow-up, and one was consistent with metastatic disease in the vertebrae.Our findings suggest that individuals identified with a germline P/LP variant in TP53 through multigene panel tests have substantial variations in clinical phenotypes not previously recognized when only those with striking family histories suggestive of LFS were tested through targeted TP53 testing. The expansion of the clinical phenotype among carriers of a P/LP in TP53 in the era of multigene testing should be considered when making cancer risk management recommendations, which were developed based on patients with classic LFS.