In‐frame variants in TP53 gene identified in adult leukemia samples are predominantly deleterious: a study of the TP53 Network of Education and Research Initiative on CLL

Abstract The prognostic and predictive impact of TP53 variants in leukemia led to their inclusion in diagnostic and treatment guidelines, increasing the demand for rapid, reliable laboratory analysis, interpretation, and reporting. While most TP53 variants identified in tumor samples can be interpreted using data from large‐scale functional studies, evidence regarding the impact of in‐frame deletions and insertions not disturbing the reading frame remains limited. Consequently, the classification of somatic in‐frame variants often relies on expert judgment rather than standardized criteria. To address this gap, we collected in‐frame TP53 variants identified during routine diagnostic testing in laboratories within the TP53 Network of Education and Research Initiative on Chronic Lymphocytic Leukemia (ERIC). We analyzed 60 leukemia samples from 13 laboratories, comprising 54 distinct variants. Initial classification using existing data and interpretation guidelines assigned these variants predominantly to the category of variants of uncertain significance. Functional analyses using a yeast‐based transactivation assay, complemented by testing selected variants in the TP53 ‐knockout RPE1 cell line, showed a nonfunctional phenotype for the vast majority of in‐frame TP53 variants. This indicates that most in‐frame alterations detected in leukemia samples are functionally deleterious, as further supported by their association with second‐allele inactivation and frequent clonal expansion in relapse. With respect to variant localization, we observed that 49 variants located within the core region of the DNA‐binding domain showed complete loss of transactivation function. The five variants located downstream of codon 286 exhibited heterogeneous functional phenotypes depending on their localization and the experimental system used. In conclusion, the integration of our findings with published functional data supports the interpretation that in‐frame TP53 variants within the core DNA‐binding domain identified in tumor samples are likely pathogenic. Conversely, interpretation of less frequent in‐frame variants outside this region requires integration of multiple evidence, including functional studies, published literature, and curated variant databases. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Journal
The Journal of Pathology
Published
2026-09-24
DOI
https://doi.org/10.1002/path.70124
Primary Topic
Chronic Lymphocytic Leukemia Research
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article
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article

In‐frame variants in TP53 gene identified in adult leukemia samples are predominantly deleterious: a study of the TP53 Network of Education and Research Initiative on CLL

Audrey Bidet, Martina Sopkovičová, Grégory Lazarian, Mònica López‐Guerra et al.
The Journal of Pathology
Chronic Lymphocytic Leukemia Research
article

In‐frame variants in TP53 gene identified in adult leukemia samples are predominantly deleterious: a study of the TP53 Network of Education and Research Initiative on CLL

Audrey Bidet, Martina Sopkovičová, Grégory Lazarian, Mònica López‐Guerra, Šárka Pavlová, Fanny Baran‐Marszak, Stephan Stilgenbauer, M. Alcoceba, Blanca Ferrer Lores, Riccardo Moia, Ivana Ježíšková, Silvia Zibellini, Jitka Malčíková, Helena Podgornik, Marcela Ženatová, Alicia Serrano‐Alcalá, Anna Panovská, Libor Macůrek, Silvia Petrezsélyová, Sandra Šućurović, Ana Balanzategui, Lisa Bonello, Šárka Pospı́šilová, Marzia Varettoni, Eva Zapletalová, Mark Catherwood, Marie Zádrapová, Johana Gombíková, Eugen Tausch
article en

Abstract

Abstract The prognostic and predictive impact of TP53 variants in leukemia led to their inclusion in diagnostic and treatment guidelines, increasing the demand for rapid, reliable laboratory analysis, interpretation, and reporting. While most TP53 variants identified in tumor samples can be interpreted using data from large‐scale functional studies, evidence regarding the impact of in‐frame deletions and insertions not disturbing the reading frame remains limited. Consequently, the classification of somatic in‐frame variants often relies on expert judgment rather than standardized criteria. To address this gap, we collected in‐frame TP53 variants identified during routine diagnostic testing in laboratories within the TP53 Network of Education and Research Initiative on Chronic Lymphocytic Leukemia (ERIC). We analyzed 60 leukemia samples from 13 laboratories, comprising 54 distinct variants. Initial classification using existing data and interpretation guidelines assigned these variants predominantly to the category of variants of uncertain significance. Functional analyses using a yeast‐based transactivation assay, complemented by testing selected variants in the TP53 ‐knockout RPE1 cell line, showed a nonfunctional phenotype for the vast majority of in‐frame TP53 variants. This indicates that most in‐frame alterations detected in leukemia samples are functionally deleterious, as further supported by their association with second‐allele inactivation and frequent clonal expansion in relapse. With respect to variant localization, we observed that 49 variants located within the core region of the DNA‐binding domain showed complete loss of transactivation function. The five variants located downstream of codon 286 exhibited heterogeneous functional phenotypes depending on their localization and the experimental system used. In conclusion, the integration of our findings with published functional data supports the interpretation that in‐frame TP53 variants within the core DNA‐binding domain identified in tumor samples are likely pathogenic. Conversely, interpretation of less frequent in‐frame variants outside this region requires integration of multiple evidence, including functional studies, published literature, and curated variant databases. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Journal of Pathology
Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Central European Institute of Technology (CZ), University of Ulster (GB), University of Ljubljana (SI), Inserm (FR), Universität Ulm (DE), Czech Academy of Sciences (CZ), Masaryk University (CZ), Ljubljana University Medical Centre (SI), Belfast City Hospital (GB), Centre Hospitalier Universitaire de Bordeaux (FR), Sorbonne Université (FR), Central European Institute of Technology – Masaryk University (CZ), Université Sorbonne Paris Nord (FR), University Hospital Foundation (CA), Hospital Clínico Universitario de Valencia (ES), Azienda Ospedaliero Universitaria San Giovanni Battista (IT), Hospital Clínic de Barcelona (ES), Hôpital Avicenne (FR), Institute of Molecular Genetics (RU), Czech Academy of Sciences, Institute of Molecular Genetics (CZ), Centro de Investigación del Cáncer (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
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Chronic Lymphocytic Leukemia Research
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