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Original research
Update of the UMD-VHL database: classification of 164 challenging variants based on genotype–phenotype correlation among 605 entries
  1. Gregory Mougel1,
  2. Amira Mohamed2,
  3. Nelly Burnichon3,
  4. Sophie Giraud4,
  5. Pascal Pigny5,
  6. Brigitte Bressac-de Paillerets6,
  7. Delphine Mirebeau-Prunier7,
  8. Alexandre Buffet3,
  9. Frédérique Savagner8,
  10. Pauline Romanet1,
  11. Yannick Arlot9,
  12. Betty Gardie10,
  13. Anne-Paule Gimenez-Roqueplo3,
  14. Christophe Beroud11,
  15. Stephane Richard12,13,
  16. Anne Barlier1
  1. 1 Aix Marseille Univ, APHM, INSERM, MMG, U1251, GEnOPé Departement, M2GM, Timone Hospital, Marseille, France
  2. 2 APHM, GEnOPé Department, M2GM, Timone Hospital, Marseille, France
  3. 3 Département de Médecine Génomique des Tumeurs et des Cancers, Hôpital européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Université Paris Cité, Inserm, PARCC, Paris, France
  4. 4 Genetics Department, Hospices Civils de Lyon (HCL), University Hospital, East Pathology Center, Lyon, France
  5. 5 Service de Biochimie et Biologie Moléculaire « Hormonologie, Métabolisme-Nutrition, Oncologie », Centre de Biologie Pathologie, CHU Lille, Bd du Pr J Leclercq, Lille, France
  6. 6 Service de Genetique, Département de Biologie et Pathologies Médicales, Gustave Roussy; INSERM U1279, Université Paris-Saclay, Villejuif Cedex, France
  7. 7 Département de Biochimie et Génétique, Service de Biochimie et Biologie Moléculaire, CHU d'Angers, University of Angers, INSERM, CNRS, MITOVASC, Equipe MitoLab, SFRICAT, Angers, France
  8. 8 Laboratoire de Biochimie, Institut Fédératif de Biologie, CHU Toulouse; Inserm UMR1297, I2MC, Toulouse, France
  9. 9 CNRS UMR6290, Université Rennes 1, SFR-UMS CNRS 3480, INSERM 018, Rennes, France
  10. 10 Ecole Pratique des Hautes Etudes, EPHE, Université PSL; Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France
  11. 11 Department of Genetics, M2GM, Timone Hospital, Aix Marseille Univ, APHM, INSERM, MMG, U1251 Bioinformatic Team, Marseille, France
  12. 12 Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France, UMR 9019-CNRS, Gustave Roussy Cancer Campus, Villejuif, France et Service d’Urologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France
  13. 13 Réseau National pour Cancers rares de l’Adulte PREDIR labellisé par l’INCa, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Paris, France
  1. Correspondence to Professor Anne Barlier, Biogenopole TIMONE, GEnOPé department, 264 rue Saint Pierre, 13385 Marseille cedex 05, France, Marseille, France; anne.barlier{at}


Background The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling.

Methods The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (

Results 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.

Conclusion 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.

  • databases, genetic
  • neoplasms
  • congenital, hereditary, and neonatal diseases and abnormalities

Data availability statement

Data are available upon reasonable request. No data are available.

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Data availability statement

Data are available upon reasonable request. No data are available.

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  • Contributors GM and AB designed the study and wrote the manuscript. All of the authors provided patients, carried out the molecular analyses and interpreted the data. NB, SG, PP, FS, PR, A-PG-R, SR and AB have revised the manuscript and have given approval for final submission. All the authors read and approved the manuscript. Guarantor: AB.

  • Funding All phases of this study were supported by grants from the Institut National de lute contre le Cancer (INCa) and the French Ministry of Health.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.