PURPOSE Multigene panel testing (MGPT) identifies TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes, of which only one is classic Li-Fraumeni syndrome. Low variant allelic fraction (VAF) in TP53 found on germline testing may suggest aberrant clonal expansion or constitutional mosaicism. We evaluated TP53-positive probands seen in a cancer genetics program to determine germline versus somatic status. METHODS We reviewed TP53-positive probands from 2012 to 2019 identified by MGPT on blood or saliva (N = 84). Available VAFs were collected. Probands with a familial variant, who met Li-Fraumeni syndrome testing criteria or who carried a founder variant, were considered germline. For those with uncertain germline status, TP53 variants were further examined using ancillary data of family members and somatic tissue. RESULTS Of the 84 probands, 54.7% had germline variants with 33.3% meeting criteria for germline status and 21.4% confirmed through ancillary testing. Aberrant clonal expansion comprised 13.1% with clonal hematopoiesis of indeterminate potential and 2.4% with a hematologic malignancy. Constitutional mosaicism was confirmed in 8.3% probands. Definitive status could not be determined in 3.6% despite ancillary assessment, and 17.9% did not have ancillary testing. CONCLUSION A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, approximately half of the patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism require intensified surveillance. A framework of multiple strategies enables discernment of germline from constitutional mosaic and acquired variants, which is essential for appropriate management.