Mosaic Li Fraumeni Syndrome Not Identified in Germinal Tissue - Open Access Clinical Report

Q: How was genetic testing performed to evaluate mosaicism in this case?

Testing used a custom gene panel with high read depth, and DNA from four tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced to compare variant allele frequencies.

Q: Why did preimplantation genetic testing not detect the TP53 variant in the embryos?

Although the peripheral blood sample showed a pathogenic TP53 variant, preimplantation genetic testing for monogenic disorders did not identify the variant in any of the nine embryos tested.

Sep 23, 2026

Uploaded by Valentina

Li Fraumeni syndrome (LFS) is a hereditary multi-cancer condition driven by TP53 alterations, and next-generation sequencing can detect TP53 variants at low variant allele frequencies (VAFs). A TP53 variant with VAF <50% may reflect mosaic LFS, aberrant clonal expansion, or circulating tumor DNA, making correct interpretation essential for patient management. The study used a custom gene panel and sequenced four tissues to assess VAF patterns.

LanguageEnglish

CategoryHealthcare

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Pages6

Reading Time15 min

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Introduction

Clinical Presentation

Methods

Results

Conclusion

Molecular Genetics & Genomic Medicine |
CLINICAL REPORT OPEN ACCESS
Mosaic Li Fraumeni Syndrome Not Identified in Germinal Tissue
Rhianna M. Urban1 | Nisha Kanwar1 | Megan A. Holdren1 | Megan F. Hoenig1 | Laura M. Rust2 | Myra J. Wick2 | Matthew J. Ferber1 | Zhiyv Niu1 | Sounak Gupta1 | Wei Shen1
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA | 2Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence: Wei Shen ([shen.wei@mayo.edu](shen.wei@mayo.edu))
Received: 6 November 2024 | Revised: 22 October 2025 | Accepted: 24 December 2025
Keywords: gonadal mosaicism | mosaic Li Fraumeni syndrome | post-zygotic mosaicism | | | --- | --- | | ABSTRACT
Background: Li Fraumeni syndrome (LFS) is a hereditary multi-cancer syndrome caused by alterations in TP53 (MIM\# 151623) . Next generation sequencing (NGS) allows for the detection of TP53 variants at lower variant allele frequencies (VAFs) . A TP53 variant with a VAF < 50% may represent mosaic LFS, aberrant clonal expansion (ACE), or possible circulating tumor DNA. Differentiation among these conditions is important for optimal patient management.
Methods: Genetic testing was performed using a custom gene panel, with an average read depth of 350× (range 166–553×) . DNA extracted from four different tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced.
Results: Here, we describe an adult female patient with a history of an adrenocortical neoplasm and osteosarcoma, diagnosed at 2 and 16 years of age, respectively. Testing of peripheral blood identified a pathogenic TP53 variant, c.733G>A, p.(Gly245Ser)(NM_ 000546.6); however, subsequent in vitro fertilization with preimplantation genetic testing for monogenic disorders (PGTM) did not identify this TP53 variant in any of nine embryos tested. Testing for possible mosaicism in the proband was performed on four different specimens, revealing variable VAFs of the TP53 variant (saliva: 44%; blood: 31%; cultured skin fibroblasts: 18%; and colon tissue: 9%). These results suggest a post-zygotic event, consistent with mosaic LFS rather than ACE.
Conclusion: This case highlights the complexity of interpreting mosaic variants in the TP53 gene, and we propose a testing algorithm to aid in the delineation of this phenomenon when relaying cancer and reproductive risk information in the context of mosaicism. | | | 1 | Introduction | Malkin et al. 1990). The hallmark feature of LFS is the development of multiple primary cancers with an early age of onset, the | | Li Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome associated with pathogenic and likely pathogenic variants in TP53 . A diverse spectrum of childhood- | average of which is approximately 14–17 years of age (Bataliniet al. 2019; Schneider et al. 1993) . | | and adult-onset malignancies are identified in affected indi- | Genetic testing for LFS is clinically indicated in individuals with | | viduals including adrenocortical carcinomas, choroid plexus | a known familial pathogenic TP53 variant, or those who meet | | carcinomas, osteosarcomas, soft-tissue sarcomas, breast can- | the classic criteria proposed by Li and Fraumeni in 1988 or the | | cers, brain cancers, and leukemias (Li and Fraumeni Jr. 1969; | Chompret criteria introduced in 2001 with ongoing revisions (Daly | | Rhianna M. Urban and Nisha Kanwar have contributed equally to this work. | | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2025 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. | | Molecular Genetics & Genomic Medicine, 2026; 14:e70178 1 of 6 [https://doi.org/10.1002/mg

FAQs

What causes diagnostic uncertainty when a TP53 variant is detected with VAF below 50%?

A TP53 variant with VAF <50% can indicate mosaic LFS, aberrant clonal expansion, or circulating tumor DNA, so multiple explanations must be distinguished for accurate care.

How was genetic testing performed to evaluate mosaicism in this case?

Testing used a custom gene panel with high read depth, and DNA from four tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced to compare variant allele frequencies.

Why did preimplantation genetic testing not detect the TP53 variant in the embryos?

Although the peripheral blood sample showed a pathogenic TP53 variant, preimplantation genetic testing for monogenic disorders did not identify the variant in any of the nine embryos tested.

Sep 23, 2026

Uploaded by Valentina