{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T07:01:39Z","timestamp":1784703699913,"version":"3.55.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004375","name":"Tel Aviv University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004375","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Familial Cancer"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Germline\n                      <jats:italic>TP53<\/jats:italic>\n                      pathogenic variants are classically associated with Li-Fraumeni syndrome, although penetrance and tumor spectrum vary substantially across specific alleles. The Ashkenazi Jewish\n                      <jats:italic>TP53<\/jats:italic>\n                      c.1000G\u2009&gt;\u2009C (p.Gly334Arg) variant has been reported as a lower-penetrance, later-onset cancer predisposition allele, but its clinical classification and penetrance remain subjects of ongoing discussion. Consequently, the optimal surveillance approach for carriers remains uncertain, and real-world surveillance outcome data are limited.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a retrospective descriptive study of heterozygous\u00a0\n                      <jats:italic>TP53<\/jats:italic>\n                      \u00a0p.Gly334Arg carriers followed at two Israeli hereditary cancer clinics between 2021 and 2025. Clinical records were reviewed for demographic data, personal and family cancer history, and surveillance outcomes. Whole-body magnetic resonance imaging (WB-MRI) findings were analyzed for carriers who underwent serial surveillance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eighteen carriers from five families were identified, all of Ashkenazi Jewish ancestry. Seven of 18 carriers (39%) had a personal history of malignancy. Breast cancer was the most common malignancy, occurring in four women, all diagnosed after age 50; available pathology showed hormone receptor-positive disease. No pediatric malignancies were observed, and none of the carriers met classic or Chompret clinical criteria for Li-Fraumeni syndrome. Ten carriers underwent serial WB-MRI surveillance, totaling 36 examinations (mean 3.6 per patient). No malignancies were detected. However, surveillance generated nine abnormal findings (0.25 per scan), all false positives, including one that led to invasive procedures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this clinic-based cohort,\n                      <jats:italic>TP53<\/jats:italic>\n                      p.Gly334Arg was observed in association with a later-onset, potentially lower-penetrance cancer phenotype and low short-term surveillance yield. These findings support phenotypic heterogeneity among\n                      <jats:italic>TP53<\/jats:italic>\n                      variants and raise questions regarding the optimal intensity of surveillance in this population; however, current data are insufficient to support modification of existing\n                      <jats:italic>TP53<\/jats:italic>\n                      surveillance protocols. Larger multicenter studies with longer follow-up are needed to define penetrance and guide genotype-informed management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10689-026-00591-y","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:04:26Z","timestamp":1784700266000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and surveillance outcomes of the TP53 c.1000G\u2009&gt;\u2009C (p.Gly334Arg) variant"],"prefix":"10.1007","volume":"25","author":[{"given":"Yehudit","family":"Peerless","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinat","family":"Bernstein-Molho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Kventsel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehavit","family":"Frenkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilach","family":"Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbal","family":"Kedar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviad","family":"Zick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Peretz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-4154","authenticated-orcid":false,"given":"Naama","family":"Halpern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"18","key":"591_CR1","first-page":"5358","volume":"48","author":"FP Li","year":"1988","unstructured":"Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358\u20135362","journal-title":"Cancer Res"},{"issue":"4985","key":"591_CR2","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1126\/science.1978757","volume":"250","author":"D Malkin","year":"1990","unstructured":"Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233\u20131238. https:\/\/doi.org\/10.1126\/science.1978757","journal-title":"Science"},{"issue":"21","key":"591_CR3","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 (2015) Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 33(21):2345\u20132352. https:\/\/doi.org\/10.1200\/JCO.2014.59.5728","journal-title":"J Clin Oncol"},{"issue":"10","key":"591_CR4","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1038\/s41431-020-0638-4PubMedPMID:32457520;PubMedCentralPMCID:PMC7609280","volume":"28","author":"T Frebourg","year":"2020","unstructured":"Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG (2020) Guidelines for the Li\u2013Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 28(10):1379\u20131386. https:\/\/doi.org\/10.1038\/s41431-020-0638-4PubMedPMID:32457520;PubMedCentralPMCID:PMC7609280","journal-title":"Eur J Hum Genet"},{"issue":"12","key":"591_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 (2021) 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 7(12):1800\u20131805. https:\/\/doi.org\/10.1001\/jamaoncol.2021.4398","journal-title":"JAMA Oncol"},{"key":"591_CR6","doi-asserted-by":"publisher","unstructured":"Kratz CP, Frone MN, Khincha PP, Hatton JN, Penkert J, James PA, et al. Urgent need to recognize that Disease-Causing TP53 variants with atypical penetrance require distinct clinical recommendations. J Natl Cancer Inst. 2026 Jan 24;djag015. https:\/\/doi.org\/10.1093\/jnci\/djag015 PubMed PMID: 41577833; PubMed Central PMCID: PMC12931289.","DOI":"10.1093\/jnci\/djag015"},{"issue":"9","key":"591_CR7","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 (2016) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol 17(9):1295\u20131305. https:\/\/doi.org\/10.1016\/S1470-2045(16)30249-2","journal-title":"Lancet Oncol"},{"issue":"10","key":"591_CR8","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1158\/1078-0432.CCR-24-3301","volume":"31","author":"MI Achatz","year":"2025","unstructured":"Achatz MI, Villani A, Bertuch AA, Bougeard G, Chang VY, Doria AS et al (2025) Update on cancer screening recommendations for individuals with Li\u2013Fraumeni syndrome. Clin Cancer Res 31(10):1831\u20131840. https:\/\/doi.org\/10.1158\/1078-0432.CCR-24-3301","journal-title":"Clin Cancer Res"},{"issue":"17","key":"591_CR9","doi-asserted-by":"publisher","first-page":"3732","DOI":"10.1158\/0008-5472.CAN-20-1390PubMedPMID:32675277;PubMedCentralPMCID:PMC7484045","volume":"80","author":"J Powers","year":"2020","unstructured":"Powers J, Pinto EM, Barnoud T, Leung JC, Martynyuk T, Kossenkov AV et al (2020) A rare TP53 mutation predominant in Ashkenazi Jews confers risk of multiple cancers. Cancer Res 80(17):3732\u20133744. https:\/\/doi.org\/10.1158\/0008-5472.CAN-20-1390PubMedPMID:32675277;PubMedCentralPMCID:PMC7484045","journal-title":"Cancer Res"},{"issue":"3","key":"591_CR10","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 (2021) Specifications of the ACMG\/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat 42(3):223\u2013236. https:\/\/doi.org\/10.1002\/humu.24152","journal-title":"Hum Mutat"},{"key":"591_CR11","unstructured":"National Center for Biotechnology Information. ClinVar: TP53 c.1000G>C (p.Gly334Arg) [VCV000182969.36]. Bethesda (MD): National Library of Medicine (US); Available from: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/182969\/. Accessed 12 Jun 2026."},{"issue":"21","key":"591_CR12","doi-asserted-by":"publisher","first-page":"4678","DOI":"10.1002\/cncr.33143","volume":"126","author":"EM Pinto","year":"2020","unstructured":"Pinto EM, Zambetti GP (2020) What 20 years of research has taught us about the TP53 p.R337H mutation. Cancer 126(21):4678\u20134686. https:\/\/doi.org\/10.1002\/cncr.33143","journal-title":"Cancer"},{"key":"591_CR13","doi-asserted-by":"publisher","first-page":"100982","DOI":"10.1016\/j.lana.2024.100982","volume":"42","author":"PAF Galante","year":"2025","unstructured":"Galante PAF, Guardia GDA, Pisani J, Sandoval RL, Barros-Filho MC, Gifoni ACLVC et al (2025) Personalized screening strategies for TP53 R337H carriers: a retrospective cohort study of tumor spectrum in Li-Fraumeni syndrome adult carriers. Lancet Reg Health Am. 42:100982. https:\/\/doi.org\/10.1016\/j.lana.2024.100982","journal-title":"Lancet Reg Health Am."},{"issue":"4","key":"591_CR14","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s10689-024-00391-2","volume":"23","author":"J Arnon","year":"2024","unstructured":"Arnon J, Zick A, Maoz M, Salaymeh N, Gugenheim A, Marouani M et al (2024) Clinical and genetic characteristics of carriers of the TP53 c.541C\u2009>\u2009T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent. Fam Cancer 23(4):531\u2013542. https:\/\/doi.org\/10.1007\/s10689-024-00391-2","journal-title":"Fam Cancer"},{"issue":"1","key":"591_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-22407-2","volume":"15","author":"A Sun Zhang","year":"2025","unstructured":"Sun Zhang A, Omran M, Arthur C, Malmgren H, Barbosa-Matos R, Seixas S et al (2025) TP53 p.R181H is enriched in the Swedish cohort (SWEP53) and associated with a distinct breast and prostate phenotype. Sci Rep 15(1):35033. https:\/\/doi.org\/10.1038\/s41598-025-22407-2","journal-title":"Sci Rep"},{"issue":"3","key":"591_CR16","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/s41379-020-0610-4","volume":"34","author":"MG Kuba","year":"2021","unstructured":"Kuba MG, Lester SC, Bowman T, Stokes SM, Taneja KL, Garber JE, Dillon DA (2021) Histopathologic features of breast cancer in Li\u2013Fraumeni syndrome. Mod Pathol Off J U S Can Acad Pathol Inc 34(3):542\u2013548. https:\/\/doi.org\/10.1038\/s41379-020-0610-4","journal-title":"Mod Pathol Off J U S Can Acad Pathol Inc"}],"container-title":["Familial Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-026-00591-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10689-026-00591-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-026-00591-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:04:28Z","timestamp":1784700268000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10689-026-00591-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":16,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["591"],"URL":"https:\/\/doi.org\/10.1007\/s10689-026-00591-y","relation":{},"ISSN":["1573-7292"],"issn-type":[{"value":"1573-7292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]},"assertion":[{"value":"22 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This research complies with ethical standards. The research was approved by the Institutional Review Board (IRB) committee of Sheba Medical Center (SM) and Hadassah Medical Center (HMC).","order":2,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"77"}}