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.
Related
- Bringing Cardiovascular Prevention into the Community: Protocol for an Observational Study of a Mosque-Based Health Initiative Combining Education and Cardiovascular Screening
- Functional analysis of NANOS protein variants identified in men with infertility employing zebrafish embryos
- Rare missense variants identified by whole-genome sequencing in men with oligoasthenoteratozoospermia: An experimental study
- Development of a multimodal health education module for dementia prevention in at-risk rural Indian elders: a SMRUTHI INDIA initiative
- An experience of online Pan-India transfusion medicine student's teaching and assessment during the COVID-19 pandemic: A new initiative in transfusion medicine education in India.
BibTeX
@article{pavlova2026inframe,
title = {{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}},
author = {Šárka Pavlová and Johana Gombíková and Silvia Petrezsélyová and Libor Macůrek and Marcela Ženatová and Marie Zádrapová and Anna Panovská and Eva Zapletalová and Blanca Ferrer Lores and Alicia Serrano Alcalá and Eugen Tausch and Stephan Stilgenbauer and Fanny Baran-Marszak and Gregory Lazarian and Miguel Alcoceba and Ana Balanzategui and Lisa Bonello and Ivana Ježíšková and Martina Sopkovičová and Silvia Zibellini and Marzia Varettoni and Audrey Bidet and Helena Podgornik and Sandra Šućurović and Riccardo Moia and Mónica López-Guerra and Mark Catherwood and Šárka Pospíšilová and Jitka Malčíková},
journal = {Journal of Pathology},
year = {2026},
month = sep,
doi = {10.1002/path.70124},
url = {https://hal.science/hal-05845549v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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
AU - Šárka Pavlová
AU - Johana Gombíková
AU - Silvia Petrezsélyová
AU - Libor Macůrek
AU - Marcela Ženatová
AU - Marie Zádrapová
AU - Anna Panovská
AU - Eva Zapletalová
AU - Blanca Ferrer Lores
AU - Alicia Serrano Alcalá
AU - Eugen Tausch
AU - Stephan Stilgenbauer
AU - Fanny Baran-Marszak
AU - Gregory Lazarian
AU - Miguel Alcoceba
AU - Ana Balanzategui
AU - Lisa Bonello
AU - Ivana Ježíšková
AU - Martina Sopkovičová
AU - Silvia Zibellini
AU - Marzia Varettoni
AU - Audrey Bidet
AU - Helena Podgornik
AU - Sandra Šućurović
AU - Riccardo Moia
AU - Mónica López-Guerra
AU - Mark Catherwood
AU - Šárka Pospíšilová
AU - Jitka Malčíková
PY - 2026
DA - 2026/09/24
JO - Journal of Pathology
DO - 10.1002/path.70124
UR - https://hal.science/hal-05845549v1
AB - 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.
SN - 0022-3417
SN - 1096-9896
ER -