Clinical management of TP53 mosaic variants found on germline genetic testing.

• Identification of TP53 pathogenic variants at lower-than-expected variant allele frequencies (VAF) for Li Fraumeni Syndrome (LFS) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH). • Constitutional mosaic LFS and clonal hematopoiesis (CH) represent completely different entities with regards to cancer risk, family implications and management. • In a cancer genetics specialty clinic, approximately 17 % of TP53 genetic testing results were "mosaic". • Ancillary tissue testing can help confirm a diagnosis of mosaic LFS. • Half of mosaic TP53 results may be postzygotic mosaicism (PZM) and half clonal hematopoiesis (CH). 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. Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]