{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T04:54:29Z","timestamp":1776574469458,"version":"3.51.2"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,1,5]],"date-time":"2025-01-05T00:00:00Z","timestamp":1736035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,5]],"date-time":"2025-01-05T00:00:00Z","timestamp":1736035200000},"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":["Eur J Hum Genet"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>We aimed to describe the clinical characteristics of families with heritable <jats:italic>TP53<\/jats:italic>-related cancer (h<jats:italic>TP53<\/jats:italic>rc) syndrome in Sweden with class 4 and 5 germline <jats:italic>TP53<\/jats:italic> variants (g<jats:italic>TP53<\/jats:italic>), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on <jats:italic>TP53<\/jats:italic> missense variants and their impact on protein conformation. 90 families with h<jats:italic>TP53<\/jats:italic>rc were initially identified in Sweden. After variant reclassification using the <jats:italic>TP53<\/jats:italic>-specific ACMG criteria, 83 families remained (176 carriers) to harbour a pathogenic (class 5) or likely pathogenic (class 4) variant in <jats:italic>TP53<\/jats:italic>. Of these, 112 carriers (64%) had a previous history of cancer, and 35 (31%) had developed more than one primary tumour. 16% of the families met the stricter criteria for Classic Li-Fraumeni syndrome, 45% the updated Chompret criteria, 35% for hereditary breast cancer (HBC), and the remaining 5% were classified as \u201cOthers\u201d. We identified 42 different g<jats:italic>TP53<\/jats:italic> variants of which 22 were missense. The most frequently observed variant was the missense c.542\u2009G\u2009&gt;\u2009A, p.R181H identified in 14\/29 (48%) of HBC families. Fifteen of the 20 informative missense variants (75%) were phenotypically predicted correctly using our previously published in silico prediction model. The <jats:italic>TP53<\/jats:italic> p.R181H was identified as a common Swedish variant predominantly associated with an HBC phenotype. Apart from this variant, there were no significant genotype-phenotype correlations. Therefore, due to phenotypic overlap it is still too early to stratify surveillance programme for different <jats:italic>TP53<\/jats:italic>-carriers.<\/jats:p>","DOI":"10.1038\/s41431-024-01753-1","type":"journal-article","created":{"date-parts":[[2025,1,5]],"date-time":"2025-01-05T10:37:18Z","timestamp":1736073438000},"page":"513-522","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Characterisation of heritable TP53-related cancer syndrome in Sweden\u2014a nationwide study of genotype-phenotype correlations in 90 families"],"prefix":"10.1038","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-6566","authenticated-orcid":false,"given":"Meis","family":"Omran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7079-1917","authenticated-orcid":false,"given":"Alexander","family":"Sun Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Poluha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Stenmark-Askmalm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fredrik","family":"Persson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Lotta","family":"Hallbeck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-2395","authenticated-orcid":false,"given":"Anna","family":"Ros\u00e9n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4352-152X","authenticated-orcid":false,"given":"Hafdis T.","family":"Helgadottir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6079-164X","authenticated-orcid":false,"given":"Emma","family":"Tham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7175-7102","authenticated-orcid":false,"given":"Svetlana","family":"Bajalica-Lagercrantz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,5]]},"reference":[{"key":"1753_CR1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/humu.10185","volume":"21","author":"JM Varley","year":"2003","unstructured":"Varley JM. Germline TP53 mutations and Li\u2010Fraumeni syndrome. Hum Mutat. 2003;21:313\u201320. https:\/\/doi.org\/10.1002\/humu.10185.","journal-title":"Hum Mutat"},{"key":"1753_CR2","doi-asserted-by":"publisher","first-page":"8287","DOI":"10.1158\/0008-5472.CAN-05-4247","volume":"66","author":"C-C Wu","year":"2006","unstructured":"Wu C-C, Shete S, Amos CI, Strong LC. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-fraumeni syndrome. Cancer Res (Chic, Ill). 2006;66:8287\u201392. https:\/\/doi.org\/10.1158\/0008-5472.CAN-05-4247.","journal-title":"Cancer Res (Chic, Ill)"},{"key":"1753_CR3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1097\/CCO.0000000000000423","volume":"30","author":"A Amadou","year":"2018","unstructured":"Amadou A, Waddington Achatz MI, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li\u2013Fraumeni syndrome. Curr Opin Oncol. 2018;30:23\u20139. https:\/\/doi.org\/10.1097\/CCO.0000000000000423.","journal-title":"Curr Opin Oncol"},{"key":"1753_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\u2013phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. lancet Oncol. 2021;22:1787\u201398. https:\/\/doi.org\/10.1016\/S1470-2045(21)00580-5.","journal-title":"lancet Oncol"},{"key":"1753_CR5","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1054\/bjoc.2000.1167","volume":"82","author":"A Chompret","year":"2000","unstructured":"Chompret A, Brugieres L, Frebourg T, Lemerle J, Bona\u00cfTi-Pellie C, Feunteun J, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J cancer. 2000;82:1932\u20137. https:\/\/doi.org\/10.1054\/bjoc.2000.1167.","journal-title":"Br J cancer"},{"key":"1753_CR6","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\u2010Fraumeni syndrome cohort. Cancer. 2016;122:3673\u201381. https:\/\/doi.org\/10.1002\/cncr.30248.","journal-title":"Cancer"},{"key":"1753_CR7","doi-asserted-by":"publisher","unstructured":"Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Human Genetics. https:\/\/doi.org\/10.1038\/s41431-020-0638-4. 2020","DOI":"10.1038\/s41431-020-0638-4"},{"key":"1753_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-023-11229-y","volume":"23","author":"A \u00d6fverholm","year":"2023","unstructured":"\u00d6fverholm A, T\u00f6rngren T, Ros\u00e9n A, Arver B, Einbeigi Z, Haraldsson K, et al. Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer. BMC cancer. 2023;23:738 https:\/\/doi.org\/10.1186\/s12885-023-11229-y.","journal-title":"BMC cancer"},{"key":"1753_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. https:\/\/doi.org\/10.1200\/JCO.2014.59.5728.","journal-title":"J Clin Oncol"},{"key":"1753_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;17:405\u201323. https:\/\/doi.org\/10.1038\/gim.2015.30.","journal-title":"Genet Med"},{"key":"1753_CR11","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, Andrade KC, et al. Specifications of the ACMG\/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat. 2021;42:223\u201336. https:\/\/doi.org\/10.1002\/humu.24152.","journal-title":"Hum Mutat"},{"key":"1753_CR12","doi-asserted-by":"publisher","first-page":"6345","DOI":"10.3390\/ijms22126345","volume":"22","author":"Y Liu","year":"2021","unstructured":"Liu Y, Axell O, van Leeuwen T, Konrat R, Kharaziha P, Larsson C, et al. Association between predicted effects of TP53 missense variants on protein conformation and their phenotypic presentation as Li-Fraumeni syndrome or hereditary breast cancer. Int J Mol Sci. 2021;22:6345 https:\/\/doi.org\/10.3390\/ijms22126345.","journal-title":"Int J Mol Sci"},{"key":"1753_CR13","first-page":"80","volume":"67","author":"G Bougeard","year":"2000","unstructured":"Bougeard G, Limacher JM, Martin C, Charbonnier F, Killian A, Delattre O, et al. Detection of 11 germline inactivating TP53 mutations and absence of TP63 and hCHK2 mutations in 17 French families with Li-Fraumeni or LI-Fraumeni-like syndrome. Am J Hum Genet. 2000;67:80.","journal-title":"Am J Hum Genet"},{"key":"1753_CR14","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1111\/cge.13564","volume":"96","author":"P Kharaziha","year":"2019","unstructured":"Kharaziha P, Ceder S, Axell O, Krall M, Fotouhi O, B\u00f6hm S, et al. Functional characterization of novel germline TP53 variants in Swedish families. Clin Genet. 2019;96:216\u201325. https:\/\/doi.org\/10.1111\/cge.13564.","journal-title":"Clin Genet"},{"key":"1753_CR15","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343. https:\/\/doi.org\/10.1038\/s41586-020-2308-7.","journal-title":"Nature"},{"key":"1753_CR16","doi-asserted-by":"crossref","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.","DOI":"10.1038\/s41588-018-0204-y"}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01753-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01753-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01753-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T08:20:20Z","timestamp":1744273220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-024-01753-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,5]]},"references-count":16,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["1753"],"URL":"https:\/\/doi.org\/10.1038\/s41431-024-01753-1","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,5]]},"assertion":[{"value":"28 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study was conducted according to the guidelines of the 1964 Declaration of Helsinki and approved by the regional ethical review board in Stockholm, approval number 2020\/02826 with the amendment 2021\/06932\/02. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and Consent to participate"}}]}}