{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:52:14Z","timestamp":1792806734621,"version":"4.5.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Germline pathogenic variants in\n                      <jats:italic>TP53<\/jats:italic>\n                      cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of\n                      <jats:italic>TP53<\/jats:italic>\n                      variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen\n                      <jats:italic>TP53<\/jats:italic>\n                      Variant Curation Expert Panel (VCEP) has updated its specifications.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of clonal hematopoiesis. Whenever feasible, the VCEP followed a data-driven approach using likelihood ratio-based quantitative analyses to guide code application and determine strength modifications, while also factoring in expert judgment. Proposed modifications were first discussed in working group meetings and then subjected to comprehensive review during monthly general VCEP meetings to reach consensus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The performance of new specifications was compared to that of the old specifications for 43 pilot variants, and led to both decreased VUS and increased certainty, with clinically meaningful classifications for 93% of variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The updated\n                      <jats:italic>TP53<\/jats:italic>\n                      specfications are expected to reduce VUS rates, increase inter-laboratory concordance, and improve medical management for individuals with germline\n                      <jats:italic>TP53<\/jats:italic>\n                      variants. The most current version is available at the ClinGen Criteria Specifications Registry (CSpec):\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/cspec.genome.network\/cspec\/ui\/svi\/svi\/GN009\" ext-link-type=\"uri\">https:\/\/cspec.genome.network\/cspec\/ui\/svi\/svi\/GN009<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-025-01536-3","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T11:03:21Z","timestamp":1761131001000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A quantitative, Bayesian-informed approach to gene-specific variant classification: Updated Expert Panel recommendations improve classification of TP53 germline variants for Li-Fraumeni syndrome"],"prefix":"10.1186","volume":"17","author":[{"given":"Cristina","family":"Fortuno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan N.","family":"Frone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Mester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"de la Hoya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong L.","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Pesaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabel","family":"Achatz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Bassett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Bustamante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Crowley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin Cesar","family":"de Andrade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Gareth","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjian","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fuqua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabel","family":"Harrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N.","family":"Hatton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Huether","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chimene","family":"Kesserwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne P.","family":"MacFarland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie L.","family":"Maciaszek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"McGoldrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Nehoray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Penkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia Modolo","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon E.","family":"Plon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Schwartz-Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley S.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard P.","family":"Zambetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Zelley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon A.","family":"Savage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"Kratz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B.","family":"Spurdle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"issue":"12","key":"1536_CR1","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1136\/jmg-2023-109464","volume":"60","author":"C Fortuno","year":"2023","unstructured":"Fortuno C, Richardson M, Pesaran T, Yussuf A, Horton C, James PA, et al. CHEK2 is not a Li-Fraumeni syndrome gene: time to update public resources. J Med Genet. 2023;60(12):1215\u20137.","journal-title":"J Med Genet"},{"issue":"21","key":"1536_CR2","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 JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33(21):2345\u201352.","journal-title":"J Clin Oncol"},{"issue":"23","key":"1536_CR3","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1002\/cncr.30248","volume":"122","author":"PL Mai","year":"2016","unstructured":"Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122(23):3673\u201381.","journal-title":"Cancer"},{"issue":"12","key":"1536_CR4","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1016\/S1470-2045(21)00580-5","volume":"22","author":"KC de Andrade","year":"2021","unstructured":"de Andrade KC, Khincha PP, Hatton JN, Frone MN, Wegman-Ostrosky T, Mai PL, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol. 2021;22(12):1787\u201398.","journal-title":"Lancet Oncol"},{"issue":"12","key":"1536_CR5","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(12):1800\u20135.","journal-title":"JAMA Oncol"},{"key":"1536_CR6","doi-asserted-by":"publisher","first-page":"e2300453","DOI":"10.1200\/PO.23.00453","volume":"8","author":"C Fortuno","year":"2024","unstructured":"Fortuno C, Feng BJ, Carroll C, Innella G, Kohlmann W, L\u00e1zaro C, et al. Cancer risks associated with TP53 pathogenic variants: maximum likelihood analysis of extended pedigrees for diagnosis of first cancers beyond the Li-fraumeni syndrome spectrum. JCO Precis Oncol. 2024;8:e2300453.","journal-title":"JCO Precis Oncol"},{"key":"1536_CR7","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.1968","author":"ML Ballinger","year":"2017","unstructured":"Ballinger ML, Best A, Mai PL, Khincha PP, Loud JT, Peters JA, et al. Baseline surveillance in Li-Fraumeni syndrome using whole-body magnetic resonance imaging: a meta-analysis. JAMA Oncol. 2017. https:\/\/doi.org\/10.1001\/jamaoncol.2017.1968.","journal-title":"JAMA Oncol"},{"issue":"9","key":"1536_CR8","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1016\/S1470-2045(16)30249-2","volume":"17","author":"A Villani","year":"2016","unstructured":"Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17(9):1295\u2013305.","journal-title":"Lancet Oncol"},{"issue":"4","key":"1536_CR9","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1007\/s10689-019-00140-w","volume":"18","author":"CM Bittar","year":"2019","unstructured":"Bittar CM, Vieira IA, Sabato CS, Andreis TF, Alemar B, Artigalas O, et al. TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling. Fam Cancer. 2019;18(4):451\u20136.","journal-title":"Fam Cancer"},{"issue":"5","key":"1536_CR10","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(5):405\u201324.","journal-title":"Genet Med"},{"issue":"23","key":"1536_CR11","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","volume":"372","author":"HL Rehm","year":"2015","unstructured":"Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, et al. ClinGen\u2013the clinical genome resource. N Engl J Med. 2015;372(23):2235\u201342.","journal-title":"N Engl J Med"},{"key":"1536_CR12","unstructured":"TP53 Variant Curation Expert Panel (VCEP). Available from: https:\/\/clinicalgenome.org\/affiliation\/50013\/. Cited 15 Aug 2025."},{"issue":"3","key":"1536_CR13","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1002\/humu.24152","volume":"42","author":"C Fortuno","year":"2021","unstructured":"Fortuno C, Lee K, Olivier M, Pesaran T, Mai PL, de Andrade KC, et al. Specifications of the ACMG\/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat. 2021;42(3):223\u201336.","journal-title":"Hum Mutat"},{"issue":"D1","key":"1536_CR14","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","volume":"46","author":"MJ Landrum","year":"2018","unstructured":"Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. Clinvar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46(D1):D1062\u20137.","journal-title":"Nucleic Acids Res"},{"key":"1536_CR15","unstructured":"The ClinGen Evidence Repository. Available from: https:\/\/erepo.clinicalgenome.org\/evrepo\/. Cited 15 Aug 2025."},{"key":"1536_CR16","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24088","author":"SV Tavtigian","year":"2020","unstructured":"Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG\/AMP variant classification guidelines. Hum Mutat. 2020. https:\/\/doi.org\/10.1002\/humu.24088.","journal-title":"Hum Mutat"},{"issue":"12","key":"1536_CR17","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","volume":"109","author":"V Pejaver","year":"2022","unstructured":"Pejaver V, Byrne AB, Feng BJ, Pagel KA, Mooney SD, Karchin R, et al. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria. Am J Hum Genet. 2022;109(12):2163\u201377.","journal-title":"Am J Hum Genet"},{"issue":"7","key":"1536_CR18","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.ajhg.2023.06.002","volume":"110","author":"LC Walker","year":"2023","unstructured":"Walker LC, Hoya M, Wiggins GAR, Lindy A, Vincent LM, Parsons MT, et al. Using the ACMG\/AMP framework to capture evidence related to predicted and observed impact on splicing: recommendations from the ClinGen SVI splicing subgroup. Am J Hum Genet. 2023;110(7):1046\u201367.","journal-title":"Am J Hum Genet"},{"key":"1536_CR19","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24060","author":"C Fortuno","year":"2020","unstructured":"Fortuno C, Mester J, Pesaran T, Weitzel JN, Dolinsky J, Yussuf A, et al. Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG\/AMP guidelines. Hum Mutat. 2020. https:\/\/doi.org\/10.1002\/humu.24060.","journal-title":"Hum Mutat"},{"issue":"3","key":"1536_CR20","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.gim.2021.10.018","volume":"24","author":"C Fortuno","year":"2022","unstructured":"Fortuno C, McGoldrick K, Pesaran T, Dolinsky J, Hoang L, Weitzel JN, et al. Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity. Genet Med. 2022;24(3):673\u201380.","journal-title":"Genet Med"},{"issue":"1","key":"1536_CR21","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(1):140\u201353.","journal-title":"Nat Genet"},{"issue":"12","key":"1536_CR22","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1038\/s41416-023-02263-5","volume":"128","author":"DG O\u2019Mahony","year":"2023","unstructured":"O\u2019Mahony DG, Ramus SJ, Southey MC, Meagher NS, Hadjisavvas A, John EM, et al. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2. Br J Cancer. 2023;128(12):2283\u201394.","journal-title":"Br J Cancer"},{"issue":"9","key":"1536_CR23","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1016\/j.ajhg.2024.07.013","volume":"111","author":"MT Parsons","year":"2024","unstructured":"Parsons MT, de la Hoya M, Richardson ME, Tudini E, Anderson M, Berkofsky-Fessler W, 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(9):2044\u201358.","journal-title":"Am J Hum Genet"},{"key":"1536_CR24","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23553","author":"C Fortuno","year":"2018","unstructured":"Fortuno C, James PA, Young EL, Feng B, Olivier M, Pesaran T, et al. Improved, ACMG-compliant, in silico prediction of pathogenicity for missense substitutions encoded by TP53 variants. Hum Mutat. 2018. https:\/\/doi.org\/10.1002\/humu.23553.","journal-title":"Hum Mutat"},{"issue":"5","key":"1536_CR25","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1038\/s41418-022-00976-3","volume":"29","author":"KC de Andrade","year":"2022","unstructured":"de Andrade KC, Lee EE, Tookmanian EM, Kesserwan CA, Manfredi JJ, Hatton JN, et al. The TP53 database: transition from the International Agency for Research on Cancer to the US National Cancer Institute. Cell Death Differ. 2022;29(5):1071\u20133.","journal-title":"Cell Death Differ"},{"key":"1536_CR26","unstructured":"Variant Curation Standard Operating Procedure, Version 3. Available from: https:\/\/www.clinicalgenome.org\/docs\/variant-curation-standard-operating-procedure-version-3\/. Cited 15 Aug 2025."},{"issue":"7993","key":"1536_CR27","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","volume":"625","author":"S Chen","year":"2024","unstructured":"Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625(7993):92\u2013100.","journal-title":"Nature"},{"key":"1536_CR28","unstructured":"ClinGen Guidance to VCEPs regarding the use of gnomAD v4. Available from: https:\/\/clinicalgenome.org\/docs\/clingen-guidance-to-vceps-regarding-the-use-of-gnomad-v4\/. Cited 15 Aug 2025."},{"issue":"11","key":"1536_CR29","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1002\/humu.23626","volume":"39","author":"AN Abou Tayoun","year":"2018","unstructured":"Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, et al. Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion. Hum Mutat. 2018;39(11):1517\u201324.","journal-title":"Hum Mutat"},{"issue":"12","key":"1536_CR30","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1038\/cdd.2011.120","volume":"18","author":"V Marcel","year":"2011","unstructured":"Marcel V, Dichtel-Danjoy ML, Sagne C, Hafsi H, Ma D, Ortiz-Cuaran S, et al. Biological functions of p53 isoforms through evolution: lessons from animal and cellular models. Cell Death Differ. 2011;18(12):1815\u201324.","journal-title":"Cell Death Differ"},{"issue":"1","key":"1536_CR31","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026047","volume":"7","author":"N Raj","year":"2017","unstructured":"Raj N, Attardi LD. The transactivation domains of the p53 protein. Cold Spring Harb Perspect Med. 2017;7(1): a026047.","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"14","key":"1536_CR32","doi-asserted-by":"publisher","first-page":"8424","DOI":"10.1073\/pnas.1431692100","volume":"100","author":"S Kato","year":"2003","unstructured":"Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003;100(14):8424\u20139.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"1536_CR33","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(10):1381\u20137.","journal-title":"Nat Genet"},{"issue":"3","key":"1536_CR34","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, et al. Predicting splicing from primary sequence with deep learning. Cell. 2019;176(3):535-48.e24.","journal-title":"Cell"},{"issue":"2\u20133","key":"1536_CR35","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1089\/1066527041410418","volume":"11","author":"G Yeo","year":"2004","unstructured":"Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol. 2004;11(2\u20133):377\u201394.","journal-title":"J Comput Biol"},{"issue":"1","key":"1536_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32887-9","volume":"13","author":"Y Shiraishi","year":"2022","unstructured":"Shiraishi Y, Okada A, Chiba K, Kawachi A, Omori I, Mateos RN, et al. Systematic identification of intron retention associated variants from massive publicly available transcriptome sequencing data. Nat Commun. 2022;13(1): 5357.","journal-title":"Nat Commun"},{"issue":"3","key":"1536_CR37","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1002\/humu.23158","volume":"38","author":"BJ Feng","year":"2017","unstructured":"Feng BJ. Perch: a unified framework for disease gene prioritization. Hum Mutat. 2017;38(3):243\u201351.","journal-title":"Hum Mutat"},{"issue":"1","key":"1536_CR38","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(1):178-90 e8.","journal-title":"Mol Cell"},{"issue":"10","key":"1536_CR39","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1002\/humu.24264","volume":"42","author":"C Fortuno","year":"2021","unstructured":"Fortuno C, Pesaran T, Dolinsky J, Yussuf A, McGoldrick K, Tavtigian SV, et al. An updated quantitative model to classify missense variants in the TP53 gene: a novel multifactorial strategy. Hum Mutat. 2021;42(10):1351\u201361.","journal-title":"Hum Mutat"},{"issue":"10","key":"1536_CR40","doi-asserted-by":"publisher","first-page":"2748","DOI":"10.1093\/emboj\/17.10.2748","volume":"17","author":"MG Mateu","year":"1998","unstructured":"Mateu MG, Fersht AR. Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain. EMBO J. 1998;17(10):2748\u201358.","journal-title":"EMBO J"},{"issue":"18","key":"1536_CR41","doi-asserted-by":"publisher","first-page":"9955","DOI":"10.1073\/pnas.160075697","volume":"97","author":"J Noolandi","year":"2000","unstructured":"Noolandi J, Davison TS, Volkel AR, Nie X, Kay C, Arrowsmith CH. A meanfield approach to the thermodynamics of a protein-solvent system with application to the oligomerization of the tumor suppressor p53. Proc Natl Acad Sci U S A. 2000;97(18):9955\u201360.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"46","key":"1536_CR42","doi-asserted-by":"publisher","first-page":"6976","DOI":"10.1038\/sj.onc.1208839","volume":"24","author":"T Kawaguchi","year":"2005","unstructured":"Kawaguchi T, Kato S, Otsuka K, Watanabe G, Kumabe T, Tominaga T, et al. The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. Oncogene. 2005;24(46):6976\u201381.","journal-title":"Oncogene"},{"issue":"2","key":"1536_CR43","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.ab.2009.01.030","volume":"387","author":"T Imagawa","year":"2009","unstructured":"Imagawa T, Terai T, Yamada Y, Kamada R, Sakaguchi K. Evaluation of transcriptional activity of p53 in individual living mammalian cells. Anal Biochem. 2009;387(2):249\u201356.","journal-title":"Anal Biochem"},{"issue":"20","key":"1536_CR44","doi-asserted-by":"publisher","first-page":"3396","DOI":"10.4161\/cc.8.20.9910","volume":"8","author":"M Muscolini","year":"2009","unstructured":"Muscolini M, Montagni E, Caristi S, Nomura T, Kamada R, Di Agostino S, et al. Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain. Cell Cycle. 2009;8(20):3396\u2013405.","journal-title":"Cell Cycle"},{"issue":"1","key":"1536_CR45","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(1):252\u20138.","journal-title":"J Biol Chem"},{"issue":"38","key":"1536_CR46","doi-asserted-by":"publisher","first-page":"15497","DOI":"10.1073\/pnas.1311126110","volume":"110","author":"G Gaglia","year":"2013","unstructured":"Gaglia G, Guan Y, Shah JV, Lahav G. Activation and control of p53 tetramerization in individual living cells. Proc Natl Acad Sci U S A. 2013;110(38):15497\u2013501.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"1536_CR47","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.molonc.2014.04.002","volume":"8","author":"V Lang","year":"2014","unstructured":"Lang V, Pallara C, Zabala A, Lobato-Gil S, Lopitz-Otsoa F, Farr\u00e1s R, et al. Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity. Mol Oncol. 2014;8(5):1026\u201342.","journal-title":"Mol Oncol"},{"issue":"12","key":"1536_CR48","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1093\/jnci\/djy114","volume":"110","author":"NW Fischer","year":"2018","unstructured":"Fischer NW, Prodeus A, Tran J, Malkin D, Gari\u00e9py J. Association between the oligomeric status of p53 and clinical outcomes in Li-Fraumeni syndrome. J Natl Cancer Inst. 2018;110(12):1418\u201321.","journal-title":"J Natl Cancer Inst"},{"issue":"2","key":"1536_CR49","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1158\/2159-8290.CD-17-0321","volume":"8","author":"MT Chang","year":"2018","unstructured":"Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, et al. Accelerating discovery of functional mutant alleles in cancer. Cancer Discov. 2018;8(2):174\u201383.","journal-title":"Cancer Discov"},{"issue":"11","key":"1536_CR50","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1002\/humu.23640","volume":"39","author":"MF Walsh","year":"2018","unstructured":"Walsh MF, Ritter DI, Kesserwan C, Sonkin D, Chakravarty D, Chao E, et al. Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes. Hum Mutat. 2018;39(11):1542\u201352.","journal-title":"Hum Mutat"},{"issue":"6","key":"1536_CR51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0099893","volume":"9","author":"J Giacomazzi","year":"2014","unstructured":"Giacomazzi J, Graudenz MS, Osorio CA, Koehler-Santos P, Palmero EI, Zagonel-Oliveira M, et al. Prevalence of the TP53 p. R337H mutation in breast cancer patients in Brazil. PLoS One. 2014;9(6): e99893.","journal-title":"PLoS One"},{"issue":"20","key":"1536_CR52","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1200\/JCO.2012.46.3711","volume":"31","author":"G Cust\u00f3dio","year":"2013","unstructured":"Cust\u00f3dio G, Parise GA, Kiesel Filho N, Komechen H, Sabbaga CC, Rosati R, et al. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol. 2013;31(20):2619\u201326.","journal-title":"J Clin Oncol"},{"issue":"21","key":"1536_CR53","doi-asserted-by":"publisher","first-page":"4678","DOI":"10.1002\/cncr.33143","volume":"126","author":"EM Pinto","year":"2020","unstructured":"Pinto EM, Zambetti GP. What 20 years of research has taught us about the TP53 p. R337H mutation. Cancer. 2020;126(21):4678\u201386.","journal-title":"Cancer"},{"key":"1536_CR54","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1038\/gim.2017.210","volume":"20","author":"SV Tavtigian","year":"2018","unstructured":"Tavtigian SV, Greenblatt MS, Harrison SM, Nussbaum RL, Prabhu SA, Boucher KM, et al. Modeling the ACMG\/AMP variant classification guidelines as a Bayesian classification framework. Genet Med. 2018;20:1054\u201360.","journal-title":"Genet Med"},{"issue":"17","key":"1536_CR55","doi-asserted-by":"publisher","first-page":"3732","DOI":"10.1158\/0008-5472.CAN-20-1390","volume":"80","author":"J Powers","year":"2020","unstructured":"Powers J, Pinto EM, Barnoud T, Leung JC, Martynyuk T, Kossenkov AV, et al. A rare TP53 mutation predominant in Ashkenazi Jews confers risk of multiple cancers. Cancer Res. 2020;80(17):3732\u201344.","journal-title":"Cancer Res"},{"key":"1536_CR56","unstructured":"ClinGen VCEP Protocol, Version 10. Available from: https:\/\/clinicalgenome.org\/site\/assets\/files\/3635\/clingen_variant_curation_expert_panel_protocol_v10_final.pdf. Cited 15 Aug 2025."},{"issue":"8","key":"1536_CR57","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1093\/jnci\/djy001","volume":"110","author":"HQ Rana","year":"2018","unstructured":"Rana HQ, Gelman R, LaDuca H, McFarland R, Dalton E, Thompson J, et al. Differences in TP53 mutation carrier phenotypes emerge from panel-based testing. J Natl Cancer Inst. 2018;110(8):863\u201370.","journal-title":"J Natl Cancer Inst"},{"issue":"8","key":"1536_CR58","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1093\/hmg\/ddae009","volume":"33","author":"C Fortuno","year":"2024","unstructured":"Fortuno C, Michailidou K, Parsons M, Dolinsky JS, Pesaran T, Yussuf A, et al. Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG\/AMP guidelines. Hum Mol Genet. 2024;33(8):724\u201332.","journal-title":"Hum Mol Genet"},{"issue":"7","key":"1536_CR59","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/j.tig.2019.04.005","volume":"35","author":"JR Ramroop","year":"2019","unstructured":"Ramroop JR, Gerber MM, Toland AE. Germline variants impact somatic events during tumorigenesis. Trends Genet. 2019;35(7):515\u201326.","journal-title":"Trends Genet"},{"issue":"1","key":"1536_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01301-9","volume":"3","author":"Y Inagaki-Kawata","year":"2020","unstructured":"Inagaki-Kawata Y, Yoshida K, Kawaguchi-Sakita N, Kawashima M, Nishimura T, Senda N, et al. Genetic and clinical landscape of breast cancers with germline BRCA1\/2 variants. Commun Biol. 2020;3(1):578.","journal-title":"Commun Biol"},{"issue":"6664","key":"1536_CR61","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(6664):eadg7492.","journal-title":"Science"},{"key":"1536_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2025.101402","volume":"27","author":"T Bergquist","year":"2025","unstructured":"Bergquist T, Stenton SL, Nadeau EAW, Byrne AB, Greenblatt MS, Harrison SM, et al. Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3\/BP4 criteria. Genet Med. 2025;27:101402.","journal-title":"Genet Med"},{"key":"1536_CR63","unstructured":"TP53 VCEP Criteria Specification Registry. Available from: https:\/\/cspec.genome.network\/cspec\/ui\/svi\/svi\/GN009. Cited 2025 Aug 15."}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-025-01536-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-025-01536-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-025-01536-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T12:03:25Z","timestamp":1761134605000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomemedicine.biomedcentral.com\/articles\/10.1186\/s13073-025-01536-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1536"],"URL":"https:\/\/doi.org\/10.1186\/s13073-025-01536-3","relation":{},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]},"assertion":[{"value":"15 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The following authors work for laboratories that offer fee-for-service testing: RH, CB, SC, LF, KM, MIH, JM, TP. The following authors have made substantial contributions to the TP53 gene-disease literature: CF, PAJ, ABS, MNF, SAS, EMP, GPZ, DGE. MNF receives royalties for product development of CancerGene Connect from Ommdom, Inc. DGE has received consultancy fees from Everything genetic Ltd. All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"128"}}