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.
Keywords: Abnormal clonal expansion; Clonal hematopoiesis; Li Fraumeni Syndrome; Pozt-zygotic mosaicism; TP53.
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