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Updated: Jun 27, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Clinical management of TP53 mosaic variants found on germline genetic testing
Abigail Ward1, Dana Farengo-Clark2, Danielle B McKenna2
1Master of Science in Genetic Counseling Program, Perelman School of Medicine, University of Pennsylvania, USA.
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.
Insights
Low variant allele frequency TP53 pathogenic variants (PVs) can indicate mosaicism or clonal hematopoiesis. Distinguishing between these conditions is crucial for Li Fraumeni Syndrome (LFS) patient management.
Area of Science:
- Genetics
- Oncology
- Clinical Diagnostics
Background:
- Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS).
- Low variant allele frequencies (VAF) in TP53 PVs may suggest postzygotic mosaicism (PZM) or clonal hematopoiesis (CH).
- Current guidelines for workup and management of low VAF TP53 PVs are lacking.
Purpose of the Study:
- To analyze the etiology of low VAF TP53 PVs.
- To differentiate between PZM and CH in patients with TP53 PVs.
- To inform clinical management strategies for individuals with TP53 PVs.
Main Methods:
- Retrospective analysis of 125 probands with TP53 PVs from an academic cancer genetics program.
- Evaluation of TP53 PVs with VAF < 30% or designated as "mosaic".
- Inclusion of clinical phenotype and ancillary tissue testing in diagnostic assessment.
Main Results:
- 17% (21/125) of probands had TP53 PVs with VAF < 30% or mosaic designation.
- Nine patients (43%) were diagnosed with PZM, consistent with LFS phenotype.
- Twelve patients (57%) were diagnosed with presumed CH (pCH), with differing clinical and testing profiles.
- Offspring testing was negative in all nine evaluated cases.
Conclusions:
- Determining the cause of low VAF TP53 PVs necessitates ancillary tissue testing and clinical evaluation.
- Differentiating between PZM and CH is critical for appropriate patient care and follow-up.
- This study highlights the importance of a comprehensive approach to managing individuals with low VAF TP53 variants.
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