Clinical management of TP53 mosaic variants found on germline genetic testing

Background Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. Patients and Methods Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. Results Twenty-one of 125 unrelated probands (17%) were found to harbor a TP53 PV with VAF<30% or a designation of “mosaic”. A diagnosis of PZM was made in nine (43%) due to a clinical phenotype consistent with LFS with (n=8) or without (n=1) positive ancillary tissue testing. Twelve patients (57%) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. Conclusions Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.