{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:08:51Z","timestamp":1791356931676,"version":"4.3.1"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":27,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["Priority Program \u2018Translational Oncology\u2019, project HerediVar\u00b4, 70114178"],"award-info":[{"award-number":["Priority Program \u2018Translational Oncology\u2019, project HerediVar\u00b4, 70114178"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["Priority Program \u2018Translational Oncology\u2019, project HerediVar\u00b4, 70114178"],"award-info":[{"award-number":["Priority Program \u2018Translational Oncology\u2019, project HerediVar\u00b4, 70114178"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["Priority Program \u2018Translational Oncology\u2019, project HerediVar, 70114178"],"award-info":[{"award-number":["Priority Program \u2018Translational Oncology\u2019, project HerediVar, 70114178"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["`TACTIC\u00b4, project number 70115201"],"award-info":[{"award-number":["`TACTIC\u00b4, project number 70115201"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Else Kr\u00f6ner Fresenius Foundation and Medical Faculty, Ulm University, for clinician scientist program"},{"name":"Structural Genomics Consortium (SGC), a registered charity"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pathogenic germline\n                    <jats:italic>TP53<\/jats:italic>\n                    variants predispose to diverse Li-Fraumeni syndrome (LFS) phenotypes and a broad cancer spectrum, whereby carriers of hypomorphic variants cluster in a cohort with attenuated disease onset and an overrepresentation of breast cancer (BC). Recently, functional assays have gained importance among the criteria used to predict the pathogenicity of hereditary breast and ovarian cancer (HBOC) risk-gene variants. Experimental assays scoring p53 functions in transcription and growth control have contributed to variant classification, yet a significant fraction of\n                    <jats:italic>TP53<\/jats:italic>\n                    variants remain of unknown significance (VUS). To understand whether non-canonical functions of p53 in the fidelity control of DNA replication may aid variant classification, we subjected 23\n                    <jats:italic>TP53<\/jats:italic>\n                    VUS and 20 control variants identified in the German Consortium for HBOC (GC-HBOC) to assays that monitor nascent DNA synthesis and recombination-mediated bypass of replication barriers. Our results reveal a clear functional separation between benign (B)\/likely benign (LB) and pathogenic (P)\/likely pathogenic (LP) variants in recombination measurements, with B\/LB variants associated with high recombination frequencies and P\/LP variants with low recombination frequencies. Importantly, 8\/23 VUS exhibited activities within the B\/LB or P\/LP ranges and therefore emerge as candidates for revised classification. Variant-specific recombination activities showed significant correlations with functional scores from four earlier studies systematically analyzing canonical p53 functions. Differently, in DNA fiber spreading assays B\/LB and P\/LP variants showed a more heterogeneous pattern and thus did not consistently recapitulate replication slow-down and acceleration observed in the presence and absence of p53, respectively. Structural modeling of separation-of-function (SOF) variants in transcription and recombination indicates varying effects on protein stability and the conformation of surface-exposed regions, affecting for example, the flexibility of Loop 1 (L1). Intriguingly, individual SOF variants suggest that loss-of-function (LOF) in recombination may drive BC, underscoring the predictive power of this assay for low-penetrance\n                    <jats:italic>TP53<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08463-0","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T11:53:45Z","timestamp":1772279625000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of non-canonical p53 functions in DNA replication and recombination for variant classification"],"prefix":"10.1038","volume":"17","author":[{"given":"Rebecca","family":"Jansche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Heitmeir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Faust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5255-0747","authenticated-orcid":false,"given":"Helmut","family":"Pospiech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Sutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8320-5081","authenticated-orcid":false,"given":"Christian","family":"Albig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-9820","authenticated-orcid":false,"given":"Finja","family":"Hennig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Janni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Schmutzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Hauke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1232-0138","authenticated-orcid":false,"given":"Andreas C.","family":"Joerger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2397-5041","authenticated-orcid":false,"given":"Lisa","family":"Wiesm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"8463_CR1","first-page":"101","volume":"10","author":"A Bellazzo","year":"2018","unstructured":"Bellazzo A, Sicari D, Valentino E, Del Sal G, Collavin L. Complexes formed by mutant p53 and their roles in breast cancer. Breast Cancer (Dove Med Press). 2018;10:101\u201312.","journal-title":"Breast Cancer (Dove Med Press)"},{"key":"8463_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188556","volume":"1876","author":"LJ Hern\u00e1ndez Borrero","year":"2021","unstructured":"Hern\u00e1ndez Borrero LJ, El-Deiry WS. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer. 2021;1876:188556.","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"8463_CR3","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.trecan.2020.01.007","volume":"6","author":"A Shahbandi","year":"2020","unstructured":"Shahbandi A, Nguyen HD, Jackson JG. TP53 mutations and outcomes in breast cancer: reading beyond the headlines. Trends Cancer. 2020;6:98\u2013110.","journal-title":"Trends Cancer"},{"key":"8463_CR4","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.7150\/thno.81847","volume":"13","author":"C Marvalim","year":"2023","unstructured":"Marvalim C, Datta A, Lee SC. Role of p53 in breast cancer progression: An insight into p53 targeted therapy. Theranostics. 2023;13:1421\u201342.","journal-title":"Theranostics"},{"key":"8463_CR5","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/s41418-022-00989-y","volume":"29","author":"MC Kennedy","year":"2022","unstructured":"Kennedy MC, Lowe SW. Mutant p53: it\u2019s not all one and the same. Cell Death Differ. 2022;29:983\u20137.","journal-title":"Cell Death Differ"},{"key":"8463_CR6","doi-asserted-by":"crossref","unstructured":"Amadou A, Waddington Achatz MI, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li\u2013Fraumeni syndrome: Cancer Biology: Edited by Pierre Hainaut 2018:23\u20139. Available from: URL: https:\/\/journals.lww.com\/co-oncology\/abstract\/2018\/01000\/revisiting_tumor_patterns_and_penetrance_in.5.aspx.","DOI":"10.1097\/CCO.0000000000000423"},{"key":"8463_CR7","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1001\/jamaoncol.2021.4398","volume":"7","author":"CP Kratz","year":"2021","unstructured":"Kratz CP, Freycon C, Maxwell KN, Nichols KE, Schiffman JD, Evans DG, et al. Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis. JAMA Oncol. 2021;7:1800\u20135.","journal-title":"JAMA Oncol"},{"key":"8463_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111296","volume":"27","author":"E Montellier","year":"2024","unstructured":"Montellier E, Lemonnier N, Penkert J, Freycon C, Blanchet S, Amadou A, et al. Clustering of TP53 variants into functional classes correlates with cancer risk and identifies different phenotypes of Li-Fraumeni syndrome. iScience. 2024;27:111296.","journal-title":"iScience"},{"key":"8463_CR9","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1200\/JCO.2014.59.5728","volume":"33","author":"G Bougeard","year":"2015","unstructured":"Bougeard G, Renaux-Petel M, Flaman J-M, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015;33:2345\u201352.","journal-title":"J Clin Oncol"},{"key":"8463_CR10","doi-asserted-by":"publisher","first-page":"2248","DOI":"10.1016\/j.ajhg.2021.11.001","volume":"108","author":"S Fayer","year":"2021","unstructured":"Fayer S, Horton C, Dines JN, Rubin AF, Richardson ME, McGoldrick K, et al. Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN. Am J Hum Genet. 2021;108:2248\u201358.","journal-title":"Am J Hum Genet"},{"key":"8463_CR11","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/humu.21627","volume":"33","author":"NM Lindor","year":"2012","unstructured":"Lindor NM, Guidugli L, Wang X, Vall\u00e9e MP, Monteiro ANA, Tavtigian S, et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012;33:8\u201321.","journal-title":"Hum Mutat"},{"key":"8463_CR12","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1002\/humu.23818","volume":"40","author":"MT Parsons","year":"2019","unstructured":"Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadal\u00f3 L, et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40:1557\u201378.","journal-title":"Hum Mutat"},{"key":"8463_CR13","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1136\/jmedgenet-2019-106368","volume":"57","author":"AN Monteiro","year":"2020","unstructured":"Monteiro AN, Bouwman P, Kousholt AN, Eccles DM, Millot GA, Masson J-Y, et al. Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation. J Med Genet. 2020;57:509\u201318.","journal-title":"J Med Genet"},{"key":"8463_CR14","doi-asserted-by":"crossref","unstructured":"Keimling M, Volcic M, Csernok A, Wieland B, D\u00f6rk T, Wiesm\u00fcller L. Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways; 2011.","DOI":"10.1096\/fj.11-185546"},{"key":"8463_CR15","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1002\/humu.23778","volume":"40","author":"A Fi\u00e9vet","year":"2019","unstructured":"Fi\u00e9vet A, Bellanger D, Rieunier G, Dubois d\u2019Enghien C, Sophie J, Calvas P, et al. Functional classification of ATM variants in ataxia-telangiectasia patients. Hum Mutat. 2019;40:1713\u201330.","journal-title":"Hum Mutat"},{"key":"8463_CR16","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1158\/1078-0432.CCR-23-0212","volume":"29","author":"L Stolarova","year":"2023","unstructured":"Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J, et al. ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. Clin Cancer Res. 2023;29:3037\u201350.","journal-title":"Clin Cancer Res"},{"key":"8463_CR17","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1158\/1078-0432.CCR-24-3936","volume":"31","author":"H Hanenberg","year":"2025","unstructured":"Hanenberg H, Zhang F, Malev N, Wiek C, Klamer BG, Nassar N, et al. Reclassification of ATM Missense Variants of Uncertain Significance by Integrating Results from Systematic Functional Assays into an ACMG Points-Based Framework. Clin Cancer Res. 2025;31:2426\u201340.","journal-title":"Clin Cancer Res"},{"key":"8463_CR18","doi-asserted-by":"crossref","unstructured":"Kawaguchi T, Kato S, Otsuka K, Watanabe G, Kumabe T, Tominaga T, et al. Kawaguchi_2005 \/\/ The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. Oncogene 2005;24:6976\u201381.","DOI":"10.1038\/sj.onc.1208839"},{"key":"8463_CR19","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1074\/jbc.M110.174698","volume":"286","author":"R Kamada","year":"2011","unstructured":"Kamada R, Nomura T, Anderson CW, Sakaguchi K. Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation. J Biol Chem. 2011;286:252\u20138.","journal-title":"J Biol Chem"},{"key":"8463_CR20","doi-asserted-by":"publisher","first-page":"8424","DOI":"10.1073\/pnas.1431692100","volume":"100","author":"S Kato","year":"2003","unstructured":"Kato S, Han S-Y, Liu W, Otsuka K, Shibata H, Kanamaru R, et al. Kato_2003 \/\/ Understanding the function\u2013structure and function\u2013mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc. Natl. Acad. Sci. USA 2003;100:8424\u20139.","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"8463_CR21","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1158\/1541-7786.MCR-10-0496","volume":"9","author":"P Monti","year":"2011","unstructured":"Monti P, Perfumo C, Bisio A, Ciribilli Y, Menichini P, Russo D, et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011;9:271\u20139.","journal-title":"Mol Cancer Res"},{"key":"8463_CR22","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1158\/1541-7786.MCR-14-0177","volume":"13","author":"DJ Lukin","year":"2015","unstructured":"Lukin DJ, Carvajal LA, Liu W, Resnick-Silverman L, Manfredi JJ. p53 Promotes cell survival due to the reversibility of its cell-cycle checkpoints. Mol Cancer Res. 2015;13:16\u201328.","journal-title":"Mol Cancer Res"},{"key":"8463_CR23","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.molcel.2018.06.012","volume":"71","author":"E Kotler","year":"2018","unstructured":"Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, et al. A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. Mol Cell. 2018;71:178\u201390.e8.","journal-title":"Mol Cell"},{"key":"8463_CR24","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1038\/s41588-018-0204-y","volume":"50","author":"AO Giacomelli","year":"2018","unstructured":"Giacomelli AO, Yang X, Lintner RE, McFarland JM, Duby M, Kim J, et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018;50:1381\u20137.","journal-title":"Nat Genet"},{"key":"8463_CR25","doi-asserted-by":"publisher","first-page":"332","DOI":"10.18632\/oncotarget.28195","volume":"13","author":"D Menendez","year":"2022","unstructured":"Menendez D, Anand JR, Murphy CC, Bell WJ, Fu J, Slepushkina N, et al. Etoposide-induced DNA damage is increased in p53 mutants: identification of ATR and other genes that influence effects of p53 mutations on Top2-induced cytotoxicity. Oncotarget. 2022;13:332\u201346.","journal-title":"Oncotarget"},{"key":"8463_CR26","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1038\/s41588-024-02039-4","volume":"57","author":"JS Funk","year":"2025","unstructured":"Funk JS, Klimovich M, Drangenstein D, Pielhoop O, Hunold P, Borowek A, et al. Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations. Nat Genet. 2025;57:140\u201353.","journal-title":"Nat Genet"},{"key":"8463_CR27","unstructured":"International Agency for Research on Cancer: World Health Organization [cited 2025]. Available from: URL: https:\/\/p53.iarc.fr\/TP53GeneVariations."},{"key":"8463_CR28","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"8463_CR29","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1016\/j.ajhg.2024.07.013","volume":"111","author":"Parsons","year":"2024","unstructured":"Parsons, La Hoya MT, de M, Richardson ME, Tudini E, Anderson M, et al. Evidence-based recommendations for gene-specific ACMG\/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel. Am J Hum Genet. 2024;111:2044\u201358.","journal-title":"Am J Hum Genet"},{"key":"8463_CR30","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1055\/a-1110-0909","volume":"80","author":"B Wappenschmidt","year":"2020","unstructured":"Wappenschmidt B, Hauke J, Faust U, Niederacher D, Wiesm\u00fcller L, Schmidt G, et al. Criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for the Classification of Germline Sequence Variants in Risk Genes for Hereditary Breast and Ovarian Cancer. Geburtshilfe Frauenheilkd. 2020;80:410\u201329.","journal-title":"Geburtshilfe Frauenheilkd"},{"key":"8463_CR31","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1055\/a-1342-5231","volume":"18","author":"J Hauke","year":"2021","unstructured":"Hauke J, Wappenschmidt B, Faust U, Niederacher D, Wiesm\u00fcller L, Schmidt G, et al. Aktualisierte Kriterien des Deutschen Konsortiums Famili\u00e4rer Brust- und Eierstockkrebs zur Klassifizierung von Keimbahn-Sequenzvarianten in Risikogenen f\u00fcr famili\u00e4ren Brust- und Eierstockkrebs. Senologie - Zeitschrift f\u00fcr Mammadiagnostik und -therapie. 2021;18:136\u201362.","journal-title":"Senologie - Zeitschrift f\u00fcr Mammadiagnostik und -therapie"},{"key":"8463_CR32","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/sj.cdd.4401903","volume":"13","author":"SA Gatz","year":"2006","unstructured":"Gatz SA, Wiesm\u00fcller L. p53 in recombination and repair. Cell Death Differ. 2006;13:1003\u201316.","journal-title":"Cell Death Differ"},{"key":"8463_CR33","doi-asserted-by":"crossref","unstructured":"Gottifredi V, Wiesm\u00fcller L. The Tip of an Iceberg: Replication-Associated Functions of the Tumor Suppressor p53. Cancers (Basel) 2018;10.","DOI":"10.3390\/cancers10080250"},{"key":"8463_CR34","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1093\/nar\/gkae061","volume":"52","author":"BA Casta\u00f1o","year":"2024","unstructured":"Casta\u00f1o BA, Schorer S, Guo Y, Calzetta NL, Gottifredi V, Wiesm\u00fcller L, et al. The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage. Nucleic Acids Res. 2024;52:3740\u201360.","journal-title":"Nucleic Acids Res"},{"key":"8463_CR35","doi-asserted-by":"publisher","first-page":"12188","DOI":"10.1093\/nar\/gkaa974","volume":"48","author":"S Biber","year":"2020","unstructured":"Biber S, Pospiech H, Gottifredi V, Wiesm\u00fcller L. Multiple biochemical properties of the p53 molecule contribute to activation of polymerase iota-dependent DNA damage tolerance. Nucleic Acids Res. 2020;48:12188\u2013203.","journal-title":"Nucleic Acids Res"},{"key":"8463_CR36","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.tig.2004.04.003","volume":"20","author":"P Bertrand","year":"2004","unstructured":"Bertrand P, Saintigny Y, Lopez BS. p53\u2019s double life: transactivation-independent repression of homologous recombination. Trends Genet. 2004;20:235\u201343.","journal-title":"Trends Genet"},{"key":"8463_CR37","doi-asserted-by":"publisher","first-page":"5362","DOI":"10.1093\/nar\/gkn503","volume":"36","author":"A Restle","year":"2008","unstructured":"Restle A, F\u00e4rber M, Baumann C, B\u00f6hringer M, Scheidtmann KH, M\u00fcller-Tidow C, et al. Dissecting the role of p53 phosphorylation in homologous recombination provides new clues for gain-of-function mutants. Nucleic Acids Res. 2008;36:5362\u201375.","journal-title":"Nucleic Acids Res"},{"key":"8463_CR38","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.celrep.2016.03.011","volume":"15","author":"CQX Yeo","year":"2016","unstructured":"Yeo CQX, Alexander I, Lin Z, Lim S, Aning OA, Kumar R, et al. p53 Maintains Genomic Stability by Preventing Interference between Transcription and Replication. Cell Reports. 2016;15:132\u201346.","journal-title":"Cell Reports"},{"key":"8463_CR39","doi-asserted-by":"publisher","first-page":"E4311","DOI":"10.1073\/pnas.1605828113","volume":"113","author":"S Hampp","year":"2016","unstructured":"Hampp S, Kiessling T, Buechle K, Mansilla SF, Thomale J, Rall M, et al. DNA damage tolerance pathway involving DNA polymerase \u03b9 and the tumor suppressor p53 regulates DNA replication fork progression. Proc Natl Acad Sci USA. 2016;113:E4311\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8463_CR40","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1016\/j.celrep.2016.10.036","volume":"17","author":"I Klusmann","year":"2016","unstructured":"Klusmann I, Rodewald S, M\u00fcller L, Friedrich M, Wienken M, Li Y, et al. p53 Activity Results in DNA Replication Fork Processivity. Cell Reports. 2016;17:1845\u201357.","journal-title":"Cell Reports"},{"key":"8463_CR41","doi-asserted-by":"publisher","first-page":"7457","DOI":"10.1093\/nar\/gkab526","volume":"49","author":"M Ihle","year":"2021","unstructured":"Ihle M, Biber S, Schroeder IS, Blattner C, Deniz M, Damia G, et al. Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices. Nucleic Acids Res. 2021;49:7457\u201375.","journal-title":"Nucleic Acids Res"},{"key":"8463_CR42","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade7997","volume":"9","author":"SF Mansilla","year":"2023","unstructured":"Mansilla SF, Bertolin AP, Venerus Arbilla S, Casta\u00f1o BA, Jahjah T, Singh JK, et al. Polymerase iota (Pol \u03b9) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability. Sci Adv. 2023;9:eade7997.","journal-title":"Sci Adv"},{"key":"8463_CR43","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1136\/jmedgenet-2014-102766","volume":"52","author":"A Jhuraney","year":"2015","unstructured":"Jhuraney A, Velkova A, Johnson RC, Kessing B, Carvalho RS, Whiley P, et al. BRCA1 Circos: a visualisation resource for functional analysis of missense variants. J Med Genet. 2015;52:224\u201330.","journal-title":"J Med Genet"},{"key":"8463_CR44","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.ccr.2012.05.015","volume":"22","author":"K Schlacher","year":"2012","unstructured":"Schlacher K, Wu H, Jasin M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1\/2. Cancer Cell. 2012;22:106\u201316.","journal-title":"Cancer Cell"},{"key":"8463_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0690-2","volume":"12","author":"SE Brnich","year":"2019","unstructured":"Brnich SE, Abou Tayoun AN, Couch FJ, Cutting GR, Greenblatt MS, Heinen CD, et al. Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework. Genome Med. 2019;12:3.","journal-title":"Genome Med"},{"key":"8463_CR46","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature. 2024;630:493\u2013500.","journal-title":"Nature"},{"key":"8463_CR47","unstructured":"PyMOL: by Schr\u00f6dinger [cited 2025 Sep 12]. Available from: URL: https:\/\/www.pymol.org\/."},{"key":"8463_CR48","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/s41418-024-01391-6","volume":"32","author":"AC Joerger","year":"2025","unstructured":"Joerger AC, Stiewe T, Soussi T. TP53: the unluckiest of genes?. Cell Death Differ. 2025;32:219\u201324.","journal-title":"Cell Death Differ"},{"key":"8463_CR49","doi-asserted-by":"publisher","first-page":"6306","DOI":"10.1128\/MCB.22.17.6306-6317.2002","volume":"22","author":"N Aky\u00fcz","year":"2002","unstructured":"Aky\u00fcz N, Boehden GS, S\u00fcsse S, Rimek A, Preuss U, Scheidtmann K-H, et al. DNA substrate dependence of p53-mediated regulation of double-strand break repair. Mol Cell Biol. 2002;22:6306\u201317.","journal-title":"Mol Cell Biol"},{"key":"8463_CR50","first-page":"615","volume":"90","author":"T Mahdi","year":"1998","unstructured":"Mahdi T, Alcalay D, Cognard C, Tanzer J, Kitzis A. Rescue of K562 cells from MDM2-modulated p53-dependent apoptosis by growth factor-induced differentiation. Biology of the Cell. 1998;90:615\u201327.","journal-title":"Biology of the Cell"},{"key":"8463_CR51","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1158\/0008-5472.CAN-25-1054","volume":"85","author":"J Gencel-Augusto","year":"2025","unstructured":"Gencel-Augusto J, Lozano G. Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect. Cancer Res. 2025;85:1955\u20136.","journal-title":"Cancer Res"},{"key":"8463_CR52","doi-asserted-by":"publisher","first-page":"4845","DOI":"10.1016\/j.jmb.2013.03.040","volume":"425","author":"H T\u00e9cher","year":"2013","unstructured":"T\u00e9cher H, Koundrioukoff S, Azar D, Wilhelm T, Carignon S, Brison O, et al. Replication Dynamics: Biases and Robustness of DNA Fiber Analysis. Journal of Molecular Biology. 2013;425:4845\u201355.","journal-title":"Journal of Molecular Biology"},{"key":"8463_CR53","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1083\/jcb.201208060","volume":"201","author":"Y Zhong","year":"2013","unstructured":"Zhong Y, Nellimoottil T, Peace JM, Knott SRV, Villwock SK, Yee JM, et al. The level of origin firing inversely affects the rate of replication fork progression. J Cell Biol. 2013;201:373\u201383.","journal-title":"J Cell Biol"},{"key":"8463_CR54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35727-y","volume":"14","author":"N Light","year":"2023","unstructured":"Light N, Layeghifard M, Attery A, Subasri V, Zatzman M, Anderson ND, et al. Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis. Nat Commun. 2023;14:77.","journal-title":"Nat Commun"},{"key":"8463_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06783-7","volume":"15","author":"Y Guo","year":"2024","unstructured":"Guo Y, Wu H, Wiesm\u00fcller L, Chen M. Canonical and non-canonical functions of p53 isoforms: potentiating the complexity of tumor development and therapy resistance. Cell Death Dis. 2024;15:412.","journal-title":"Cell Death Dis"},{"key":"8463_CR56","unstructured":"ClinGen TP53 Expert Panel Specifications to the ACMG\/AMP Variant Interpretation Guidelines for TP53 Version 2.3.0. Available from: URL: https:\/\/cspec.genome.network\/cspec\/ui\/svi\/doc\/GN009?version=2.3.0."},{"key":"8463_CR57","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/0092-8674(90)90113-S","volume":"62","author":"D Michalovitz","year":"1990","unstructured":"Michalovitz D, Halevy O, Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell. 1990;62:671\u201380.","journal-title":"Cell"},{"key":"8463_CR58","doi-asserted-by":"publisher","first-page":"3032","DOI":"10.1128\/MCB.15.6.3032","volume":"15","author":"LB Owen-Schaub","year":"1995","unstructured":"Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas\/APO-1 expression. Mol Cell Biol. 1995;15:3032\u201340.","journal-title":"Mol Cell Biol"},{"key":"8463_CR59","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492","volume":"381","author":"J Cheng","year":"2023","unstructured":"Cheng J, Novati G, Pan J, Bycroft C, \u017demgulyt\u0117 A, Applebaum T, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science. 2023;381:eadg7492.","journal-title":"Science"},{"key":"8463_CR60","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1002\/ijc.35475","volume":"157","author":"E Kasper","year":"2025","unstructured":"Kasper E, Boulouard F, Basset N, Golmard L, Sassi H, Bouvignies E, et al. Deciphering dual clinical entities associated with TP53 pathogenic variants: Insights from 53,085 HBOC panel analyses in French laboratories. Int J Cancer. 2025;157:897\u2013907.","journal-title":"Int J Cancer"},{"key":"8463_CR61","doi-asserted-by":"crossref","unstructured":"M\u00fcntnich LJ, Dutzmann CM, Gro\u00dfhennig A, H\u00e4rter V, Keymling M, Mastronuzzi A, et al. Cancer risk in carriers of TP53 germline variants grouped into different functional categories. JNCI Cancer Spectr 2025;9.","DOI":"10.1093\/jncics\/pkaf008"},{"key":"8463_CR62","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1007\/s00439-017-1845-0","volume":"136","author":"AK Siraj","year":"2017","unstructured":"Siraj AK, Masoodi T, Bu R, Parvathareddy SK, Al-Badawi IA, Al-Sanea N, et al. Expanding the spectrum of germline variants in cancer. Hum Genet. 2017;136:1431\u201344.","journal-title":"Hum Genet"},{"key":"8463_CR63","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s13053-021-00206-w","volume":"19","author":"AK Siraj","year":"2021","unstructured":"Siraj AK, Masoodi T, Bu R, Parvathareddy SK, Iqbal K, Azam S, et al. Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients. Hered Cancer Clin Pract. 2021;19:49.","journal-title":"Hered Cancer Clin Pract"},{"key":"8463_CR64","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1055\/a-2127-9292","volume":"131","author":"JH Kim","year":"2023","unstructured":"Kim JH, Choi Y, Hwang S, Yoon J-H, Kim G-H, Yoo H-W, et al. Clinical Characteristics and Long-Term Outcomes of Adrenal Tumors in Children and Adolescents. Exp Clin Endocrinol Diabetes. 2023;131:515\u201322.","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"8463_CR65","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1093\/neuonc\/noaa267","volume":"23","author":"C Thomas","year":"2021","unstructured":"Thomas C, Soschinski P, Zwaig M, Oikonomopoulos S, Okonechnikov K, Pajtler KW, et al. The genetic landscape of choroid plexus tumors in children and adults. Neuro-Oncology. 2021;23:650\u201360.","journal-title":"Neuro-Oncology"},{"key":"8463_CR66","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1093\/emboj\/cdf383","volume":"21","author":"DJ Derbyshire","year":"2002","unstructured":"Derbyshire DJ, Basu BP, Serpell LC, Joo WS, Date T, Iwabuchi K, et al. Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor. EMBO J. 2002;21:3863\u201372.","journal-title":"EMBO J"},{"key":"8463_CR67","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.4161\/cc.8.10.8548","volume":"8","author":"J Ahn","year":"2009","unstructured":"Ahn J, Poyurovsky MV, Baptiste N, Beckerman R, Cain C, Mattia M, et al. Dissection of the sequence-specific DNA binding and exonuclease activities reveals a superactive yet apoptotically impaired mutant p53 protein. Cell Cycle. 2009;8:1603\u201315.","journal-title":"Cell Cycle"},{"key":"8463_CR68","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/j.molcel.2006.05.015","volume":"22","author":"M Kitayner","year":"2006","unstructured":"Kitayner M, Rozenberg H, Kessler N, Rabinovich D, Shaulov L, Haran TE, et al. Structural basis of DNA recognition by p53 tetramers. Mol Cell. 2006;22:741\u201353.","journal-title":"Mol Cell"},{"key":"8463_CR69","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1038\/emboj.2011.127","volume":"30","author":"TJ Petty","year":"2011","unstructured":"Petty TJ, Emamzadah S, Costantino L, Petkova I, Stavridi ES, Saven JG, et al. An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity. EMBO J. 2011;30:2167\u201376.","journal-title":"EMBO J"},{"key":"8463_CR70","doi-asserted-by":"publisher","first-page":"3013","DOI":"10.1016\/j.jmb.2016.06.009","volume":"428","author":"R Vainer","year":"2016","unstructured":"Vainer R, Cohen S, Shahar A, Zarivach R, Arbely E. Structural Basis for p53 Lys120-Acetylation-Dependent DNA-Binding Mode. Journal of Molecular Biology. 2016;428:3013\u201325.","journal-title":"Journal of Molecular Biology"},{"key":"8463_CR71","doi-asserted-by":"publisher","first-page":"8251","DOI":"10.1073\/pnas.1105028108","volume":"108","author":"E Arbely","year":"2011","unstructured":"Arbely E, Natan E, Brandt T, Allen MD, Veprintsev DB, Robinson CV, et al. Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt concentration. Proc Natl Acad Sci USA. 2011;108:8251\u20136.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8463_CR72","doi-asserted-by":"crossref","unstructured":"Calzetta NL, Mansilla SF, Ahlers CM, Bertolin AP, Caimi LI, Arbilla SV, et al. Endogenous p21 levels protect genomic stability by suppressing both excess and restrained nascent DNA syntheses. Sci Adv 2025;1\u201318.","DOI":"10.1126\/sciadv.adw4618"},{"key":"8463_CR73","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41580-020-0257-5","volume":"21","author":"M Berti","year":"2020","unstructured":"Berti M, Cortez D, Lopes M. The plasticity of DNA replication forks in response to clinically relevant genotoxic stress. Nat Rev Mol Cell Biol. 2020;21:633\u201351.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8463_CR74","doi-asserted-by":"crossref","unstructured":"Pitolli C, Wang Y, Mancini M, Shi Y, Melino G, Amelio I. Do Mutations Turn p53 into an Oncogene? Int J Mol Sci 2019;20.","DOI":"10.3390\/ijms20246241"},{"key":"8463_CR75","doi-asserted-by":"crossref","unstructured":"Chiang Y-T, Chien Y-C, Lin Y-H, Wu H-H, Lee D-F, Yu Y-L .The Function of the Mutant p53-R175H in Cancer. Cancers (Basel) 2021;13.","DOI":"10.3390\/cancers13164088"},{"key":"8463_CR76","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1158\/2159-8290.CD-23-0402","volume":"14","author":"Z Wang","year":"2024","unstructured":"Wang Z, Burigotto M, Ghetti S, Vaillant F, Tan T, Capaldo BD, et al. Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells. Cancer Discovery. 2024;14:362\u201379.","journal-title":"Cancer Discovery"},{"key":"8463_CR77","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111568","volume":"41","author":"E Panatta","year":"2022","unstructured":"Panatta E, Butera A, Mammarella E, Pitolli C, Mauriello A, Leist M, et al. Metabolic regulation by p53 prevents R-loop-associated genomic instability. Cell Reports. 2022;41:111568.","journal-title":"Cell Reports"},{"key":"8463_CR78","doi-asserted-by":"crossref","unstructured":"Blanden AR, Yu X, Blayney AJ, Demas C, Ha J-H, Liu Y, et al. Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants. Elife 2020;9.","DOI":"10.7554\/eLife.61487"},{"key":"8463_CR79","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/bip.22772","volume":"106","author":"R Kamada","year":"2016","unstructured":"Kamada R, Toguchi Y, Nomura T, Imagawa T, Sakaguchi K. Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. Biopolymers. 2016;106:598\u2013612.","journal-title":"Biopolymers"},{"key":"8463_CR80","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1002\/humu.20880","volume":"29","author":"SE Plon","year":"2008","unstructured":"Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008;29:1282\u201391.","journal-title":"Hum Mutat"},{"key":"8463_CR81","unstructured":"ENIGMA Evidence-based Network for the interpretation of germline mutant allels. Available from: URL: https:\/\/enigmaconsortium.org\/."},{"key":"8463_CR82","unstructured":"ClinGen Clinical Genome Ressource: Clinical Domain Working Groups [TP53 variant curation expert panel] [cited 2025 Sep 11]. Available from: URL: https:\/\/clinicalgenome.org\/affiliation\/50013."},{"key":"8463_CR83","unstructured":"Deutsches Konsortium Famili\u00e4rer Brust- und Eierstockkrebs: Etabliert durch die Deutsche Krebshilfe [cited 2025 Sep 11]. Available from: URL: https:\/\/www.konsortium-familiaerer-brustkrebs.de\/informationen\/aktuelles\/detailansicht\/neues-register-fuer-mehr-wissen-zum-familiaeren-brust-und-eierstockkrebs\/; Engel 2021 Gesundheitswesen."},{"key":"8463_CR84","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.str.2009.11.011","volume":"18","author":"Y Chen","year":"2010","unstructured":"Chen Y, Dey R, Chen L. Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer. Structure. 2010;18:246\u201356.","journal-title":"Structure"},{"key":"8463_CR85","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.jmb.2011.03.047","volume":"409","author":"E Natan","year":"2011","unstructured":"Natan E, Baloglu C, Pagel K, Freund SMV, Morgner N, Robinson CV, et al. Interaction of the p53 DNA-binding domain with its n-terminal extension modulates the stability of the p53 tetramer. Journal of Molecular Biology. 2011;409:358\u201368.","journal-title":"Journal of Molecular Biology"},{"key":"8463_CR86","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1126\/science.7878469","volume":"267","author":"PD Jeffrey","year":"1995","unstructured":"Jeffrey PD, Gorina S, Pavletich NP. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science. 1995;267:1498\u2013502.","journal-title":"Science"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08463-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08463-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08463-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:04:46Z","timestamp":1774623886000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08463-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,28]]},"references-count":86,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8463"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08463-0","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,28]]},"assertion":[{"value":"22 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"JH received support from the AGO study group (AGO Research GmbH) and a honorarium from Astra Zeneca for his scientific presentation in 2024. All the other authors declare no competing financial interests in relation to the work described.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. The study was approved by the ethics committee of the University Clinic Cologne, Germany (approval\/registration number: 19-1360_4 7 \u201cHerediCaRe\u201d). Informed consent was obtained from all participants included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval and Consent to Participate"}}],"article-number":"292"}}