{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:59:19Z","timestamp":1790305159191,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["DRO 65269705"],"award-info":[{"award-number":["DRO 65269705"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009553","name":"Agentura Pro Zdravotnick\u00fd V\u00fdzkum \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["NW24\u201003\u201000114"],"award-info":[{"award-number":["NW24\u201003\u201000114"]}],"id":[{"id":"10.13039\/501100009553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001823","name":"Ministerstvo \u0160kolstv\u00ed, Ml\u00e1de\u017ee a T\u011blov\u00fdchovy","doi-asserted-by":"publisher","award":["MUNI\/A\/1733\/2025"],"award-info":[{"award-number":["MUNI\/A\/1733\/2025"]}],"id":[{"id":"10.13039\/501100001823","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The prognostic and predictive impact of\n                    <jats:italic>TP53<\/jats:italic>\n                    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\n                    <jats:italic>TP53<\/jats:italic>\n                    variants identified in tumor samples can be interpreted using data from large\u2010scale functional studies, evidence regarding the impact of in\u2010frame deletions and insertions not disturbing the reading frame remains limited. Consequently, the classification of somatic in\u2010frame variants often relies on expert judgment rather than standardized criteria. To address this gap, we collected in\u2010frame\n                    <jats:italic>TP53<\/jats:italic>\n                    variants identified during routine diagnostic testing in laboratories within the\n                    <jats:italic>TP53<\/jats:italic>\n                    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\u2010based transactivation assay, complemented by testing selected variants in the\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010knockout RPE1 cell line, showed a nonfunctional phenotype for the vast majority of in\u2010frame\n                    <jats:italic>TP53<\/jats:italic>\n                    variants. This indicates that most in\u2010frame alterations detected in leukemia samples are functionally deleterious, as further supported by their association with second\u2010allele 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\u2010binding 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\u2010frame\n                    <jats:italic>TP53<\/jats:italic>\n                    variants within the core DNA\u2010binding domain identified in tumor samples are likely pathogenic. Conversely, interpretation of less frequent in\u2010frame variants outside this region requires integration of multiple evidence, including functional studies, published literature, and curated variant databases. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70124","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:24:07Z","timestamp":1790303047000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In\u2010frame variants in\n                    <scp>\n                      <i>TP53<\/i>\n                    <\/scp>\n                    gene identified in adult leukemia samples are predominantly deleterious: a study of the\n                    <scp>\n                      <i>TP53<\/i>\n                    <\/scp>\n                    Network of Education and Research Initiative on\n                    <scp>CLL<\/scp>"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1528-9743","authenticated-orcid":false,"given":"\u0160\u00e1rka","family":"Pavlov\u00e1","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"},{"name":"Institute of Medical Genetics and Genomics University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"},{"name":"Central European Institute of Technology (CEITEC) Masaryk University  Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7139-4820","authenticated-orcid":false,"given":"Johana","family":"Gomb\u00edkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3054-540X","authenticated-orcid":false,"given":"Silvia","family":"Petrezs\u00e9lyov\u00e1","sequence":"additional","affiliation":[{"name":"Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0987-1238","authenticated-orcid":false,"given":"Libor","family":"Mac\u016frek","sequence":"additional","affiliation":[{"name":"Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-6085","authenticated-orcid":false,"given":"Marcela","family":"\u017denatov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Z\u00e1drapov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4955-3039","authenticated-orcid":false,"given":"Anna","family":"Panovsk\u00e1","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Zapletalov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hematology and Oncology University Hospital Brno and Medical Faculty, Masaryk University  Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-7310","authenticated-orcid":false,"given":"Blanca Ferrer","family":"Lores","sequence":"additional","affiliation":[{"name":"Hematology Department Hospital Cl\u00ednico Universitario\u2010INCLIVA Valencia  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3392-4336","authenticated-orcid":false,"given":"Alicia Serrano","family":"Alcal\u00e1","sequence":"additional","affiliation":[{"name":"Hematology Department Hospital Cl\u00ednico Universitario\u2010INCLIVA Valencia  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Tausch","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-9296","authenticated-orcid":false,"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3723-2927","authenticated-orcid":false,"given":"Fanny","family":"Baran\u2010Marszak","sequence":"additional","affiliation":[{"name":"GHUPSSD H\u00f4pital Avicenne AP\u2010HP  Bobigny France"},{"name":"INSERM U978 Universit\u00e9 Sorbonne Paris Nord  Bobigny 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