{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T01:36:35Z","timestamp":1794015395493,"version":"4.8.0"},"reference-count":31,"publisher":"BMJ","issue":"4","funder":[{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["70000"],"award-info":[{"award-number":["70000"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,10,28]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in <jats:italic>VHL<\/jats:italic> tumour suppressor gene. The identification of <jats:italic>VHL<\/jats:italic> variants requires accurate classification which has an impact on patient management and genetic counselling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected <jats:italic>VHL<\/jats:italic> genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing <jats:italic>VHL<\/jats:italic> genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.umd.be\/VHL\/\">http:\/\/www.umd.be\/VHL\/<\/jats:ext-link>).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109550","type":"journal-article","created":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T13:20:40Z","timestamp":1700313640000},"page":"378-384","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Update of the UMD-VHL database: classification of 164 challenging variants based on genotype\u2013phenotype correlation among 605 entries"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9753-3289","authenticated-orcid":false,"given":"Gregory","family":"Mougel","sequence":"first","affiliation":[{"name":"Aix Marseille Univ, APHM, INSERM, MMG, U1251, GEnOP\u00e9 Departement, M2GM, Timone Hospital, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Mohamed","sequence":"additional","affiliation":[{"name":"APHM, GEnOP\u00e9 Department, M2GM, Timone Hospital, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Burnichon","sequence":"additional","affiliation":[{"name":"D\u00e9partement de M\u00e9decine G\u00e9nomique des Tumeurs et des Cancers, H\u00f4pital europ\u00e9en Georges Pompidou, Assistance Publique H\u00f4pitaux de Paris, Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Giraud","sequence":"additional","affiliation":[{"name":"Genetics Department, Hospices Civils de Lyon (HCL), University Hospital, East Pathology Center, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3926-4487","authenticated-orcid":false,"given":"Pascal","family":"Pigny","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Biologie Mol\u00e9culaire \u00ab Hormonologie, M\u00e9tabolisme-Nutrition, Oncologie \u00bb, Centre de Biologie Pathologie, CHU Lille, Bd du Pr J Leclercq, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Bressac-de Paillerets","sequence":"additional","affiliation":[{"name":"Service de Genetique, D\u00e9partement de Biologie et Pathologies M\u00e9dicales, Gustave Roussy; INSERM U1279, Universit\u00e9 Paris-Saclay, Villejuif Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Mirebeau-Prunier","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biochimie et G\u00e9n\u00e9tique, Service de Biochimie et Biologie Mol\u00e9culaire, CHU d'Angers, University of Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFRICAT, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Buffet","sequence":"additional","affiliation":[{"name":"D\u00e9partement de M\u00e9decine G\u00e9nomique des Tumeurs et des Cancers, H\u00f4pital europ\u00e9en Georges Pompidou, Assistance Publique H\u00f4pitaux de Paris, Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Savagner","sequence":"additional","affiliation":[{"name":"Laboratoire de Biochimie, Institut F\u00e9d\u00e9ratif de Biologie, CHU Toulouse; Inserm UMR1297, I2MC, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Romanet","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, APHM, INSERM, MMG, U1251, GEnOP\u00e9 Departement, M2GM, Timone Hospital, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Arlot","sequence":"additional","affiliation":[{"name":"CNRS UMR6290, Universit\u00e9 Rennes 1, SFR-UMS CNRS 3480, INSERM 018, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Gardie","sequence":"additional","affiliation":[{"name":"Ecole Pratique des Hautes Etudes, EPHE, Universit\u00e9 PSL; Universit\u00e9 de Nantes, CNRS, INSERM, l\u2019institut du thorax, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Paule","family":"Gimenez-Roqueplo","sequence":"additional","affiliation":[{"name":"D\u00e9partement de M\u00e9decine G\u00e9nomique des Tumeurs et des Cancers, H\u00f4pital europ\u00e9en Georges Pompidou, Assistance Publique H\u00f4pitaux de Paris, Universit\u00e9 Paris Cit\u00e9, Inserm, PARCC, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Beroud","sequence":"additional","affiliation":[{"name":"Department of Genetics, M2GM, Timone Hospital, Aix Marseille Univ, APHM, INSERM, MMG, U1251 Bioinformatic Team, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9859-9773","authenticated-orcid":false,"given":"Stephane","family":"Richard","sequence":"additional","affiliation":[{"name":"Ecole Pratique des Hautes Etudes, EPHE, Universit\u00e9 PSL, France, UMR 9019-CNRS, Gustave Roussy Cancer Campus, Villejuif, France et Service d\u2019Urologie, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Bic\u00eatre, Le Kremlin-Bic\u00eatre, Paris, France"},{"name":"R\u00e9seau National pour Cancers rares de l\u2019Adulte PREDIR labellis\u00e9 par l\u2019INCa, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Bic\u00eatre, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Barlier","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, APHM, INSERM, MMG, U1251, GEnOP\u00e9 Departement, M2GM, Timone Hospital, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,11,18]]},"reference":[{"key":"2025100511292517000_61.4.378.1","doi-asserted-by":"publisher","DOI":"10.15586\/jkcvhl.2017.88"},{"key":"2025100511292517000_61.4.378.2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202473"},{"key":"2025100511292517000_61.4.378.3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-03-838235"},{"key":"2025100511292517000_61.4.378.4","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6144"},{"key":"2025100511292517000_61.4.378.5","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.9.3141-3151.2003"},{"key":"2025100511292517000_61.4.378.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073440"},{"key":"2025100511292517000_61.4.378.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.15.8507"},{"key":"2025100511292517000_61.4.378.8","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.175"},{"key":"2025100511292517000_61.4.378.9","doi-asserted-by":"publisher","DOI":"10.1006\/bcmd.2002.0488"},{"key":"2025100511292517000_61.4.378.10","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl362"},{"key":"2025100511292517000_61.4.378.11","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/s41431-022-01157-z","article-title":"Minors at risk of von Hippel-Lindau disease: 10 years\u2019 experience of predictive genetic testing and follow-up adherence","volume":"30","author":"Vibert","year":"2022","journal-title":"Eur J Hum Genet"},{"key":"2025100511292517000_61.4.378.12","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025100511292517000_61.4.378.13","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41431-020-00755-z","article-title":"Mobidetails: online DNA variants interpretation","volume":"29","author":"Baux","year":"2021","journal-title":"Eur J Hum Genet"},{"key":"2025100511292517000_61.4.378.14","doi-asserted-by":"crossref","DOI":"10.1038\/srep31128","article-title":"VHLdb: a database of von Hippel-Lindau protein interactors and mutations","volume":"6","author":"Tabaro","year":"2016","journal-title":"Sci Rep"},{"key":"2025100511292517000_61.4.378.15","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41379-019-0343-4","article-title":"Carbonic Anhydrase 9 immunohistochemistry as a tool to predict or validate germline and somatic VHL mutations in pheochromocytoma and Paraganglioma\u2014a retrospective and prospective study","volume":"33","author":"Favier","year":"2020","journal-title":"Mod Pathol"},{"key":"2025100511292517000_61.4.378.16","first-page":"2185","article-title":"Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene","volume":"10","author":"Kuzmin","year":"1995","journal-title":"Oncogene"},{"key":"2025100511292517000_61.4.378.17","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.7.463"},{"key":"2025100511292517000_61.4.378.18","doi-asserted-by":"publisher","DOI":"10.1086\/302726"},{"key":"2025100511292517000_61.4.378.19","doi-asserted-by":"crossref","DOI":"10.1038\/s41525-022-00291-3","article-title":"VHL mosaicism: the added value of multi-tissue analysis","volume":"7","author":"Oldfield","year":"2022","journal-title":"NPJ Genom 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gene in the ccRCC","volume":"127","author":"Chesnel","year":"2022","journal-title":"Br J Cancer"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109550","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T18:29:32Z","timestamp":1759688972000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,18]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,3,21]]},"published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1136\/jmg-2023-109550"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109550","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,18]]}}}