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Cancer genetics
Original research
Classification of PTEN germline non-truncating variants: a new approach to interpretation
  1. Henri Margot1,
  2. Natalie Jones2,
  3. Thibaut Matis2,
  4. Dominique Bonneau3,4,
  5. Tiffany Busa5,
  6. Françoise Bonnet2,
  7. Solene Conrad6,
  8. Louise Crivelli7,
  9. Pauline Monin8,
  10. Sandra Fert-Ferrer9,
  11. Isabelle Mortemousque10,
  12. Sabine Raad2,
  13. Didier Lacombe11,12,
  14. Frédéric Caux13,
  15. Nicolas Sevenet2,14,
  16. Virginie Bubien2,
  17. Michel Longy2,14
  18. French Cowden Disease Network
    1. 1Medical Genetics Departement, CHU de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France
    2. 2Cancer Genetics Unit, Institut Bergonié, Bordeaux, Aquitaine, France
    3. 3U771-CNRS6214, UMR INSERM, Angers, France
    4. 4School of Medicine, University of Angers, Angers, France
    5. 5Medical Genetics Departement, Marseille Public University Hospital System, Marseille, France
    6. 6Medical Genetics Departement, University Hospital Centre Nantes, Nantes, Pays de la Loire, France
    7. 7Department of Oncogenetics, Centre Eugene Marquis, Rennes, Bretagne, France
    8. 8Medical Genetics Departement, Centre Hospitalier Universitaire de Lyon, Lyon, Rhône-Alpes, France
    9. 9Medical Genetics Departement, Centre Hospitalier Métropole Savoie, Chambery, France
    10. 10Cancer Genetics Unit, Centre Hospitalier Régional Universitaire de Tours, Tours, Centre-Val de Loire, France
    11. 11Department of Medical Genetics, CHU Bordeaux GH Pellegrin, Bordeaux, Aquitaine, France
    12. 12MRGM INSERM U1211, Universite de Bordeaux College Sciences de la Sante, Bordeaux, Nouvelle-Aquitaine, France
    13. 13Hospital Avicenne Internal Medicine Service, Bobigny, Île-de-France, France
    14. 14UMR1312, INSERM, BoRdeaux Institute of onCology, Bordeaux, France
    1. Correspondence to Dr Virginie Bubien; v.bubien{at}bordeaux.unicancer.fr

    Abstract

    Background PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from PTEN pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel.

    Methods Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating PTEN variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency.

    Results This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance.

    Conclusion This report proposes a revision of the current PTEN variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of PTEN is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.

    • Genetics, Medical
    • Genetic Predisposition to Disease
    • Mutation, Missense

    Data availability statement

    Data are available upon reasonable request.

    https://doi.org/10.1136/jmg-2024-109982

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      Data availability statement

      Data are available upon reasonable request.

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      Footnotes

      • Collaborators Stéphanie Arpin, Department of Genetics, CHRU, Tours, France; Eric Bieth, Department of Genetics, CHU, Toulouse, France; Valérie Bonadona, Cancer Genetics Department, Centre Léon Bérard, Lyon, France; Simon Boussion, Department of Genetics, CHU, Lille, France; Bruno Buecher, Department of Genetics, PSL University, Institut Curie, Paris, France; Olivier Caron, Gustave Roussy, Cancer Genetics department, Villejuif, France; Jean Chiesa, Department of Genetics, CHRU, Nimes, France; Carole Corsini, Cancer Genetics department, CHU Montpellier, Université Montpellier, France; Louise Crivelli, Centre Eugène Marquis, Rennes, France; Rodolphe DARD, Department of Genetics, CHI de Poissy-St Germain en Laye, Poissy, France; Benjamin Dauriat, Department of Genetics, CHU Limoges, France; Capucine Delnatte, Cancer Genetics department, CHU Nantes, France; Philippe Denizeau, Cancer Genetics department, CHU Rennes, France; Florence Demurger, Department of Genetics, Centre Hospitalier Bretagne Atlantique, Vannes, France; Vincent des Portes, Department of Neuropeadiatrics, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; Anne Dieux-Coeslier, Department of Genetics, CHU Lille, France; Berenice Doray, Department of Genetics, CHU la Réunion, Hôpital Félix Guyon, Saint-Denis, France; Valérie Drouin Garraud, Department of Pediatrics, CHU Rouen, France; Nelly Durand, Department of Genetics, CHU Estaing, Clermont-Ferrand, France; Charles Patrick Edery, Department of Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; Laurence Faivre, Department of Genetics, CHU Dijon, France; Christine Francannet, Department of Genetics, CHU Estaing, Clermont-Ferrand, France; Céline Garrec, Department of Genetics, CHU de Nantes, Nantes, France, Marion Gauthier-Villars, Department of Genetics, Institut Curie, Paris, France; Marion Gerard, Department of Genetics, CHU Caen, France; Brigitte Gilbert-Dussardier, Department of Genetics, CHU Poitiers, France; Irina Giurgea, Genetics Lab, CHIC, Créteil, France; Elodie Haser, Department of Genetics, CHU Strasbourg, France; Marion Imbert-Bouteille, Cancer Genetics department, CHU Montpellier, France; Bertrand Isidor, Medical Genetic department, CHU Nantes, France; Valerie Layet, Department of Cytogenetics, CHU Rouen, France; Sophie Lejeune, Medical Genetics Department, CHRU, Lille, France; Dominique Leroux, Medical Genetics Department, CHU Grenoble, France; Stanislas, Lyonnet, Medical Genetics Department, Hôpital Necker-Enfants Malades, Paris, France; Dominique Martin Coignard, Department of Medical Genetics, Le Mans Hospital, France; Tanguy Martin-Denavit, Department of Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; Christine Maugard, Cancer Genetics department, CHU Strasbourg, France; Nicolas Molko, Department of Neurology, Territorial Hospital of Noumea, New Caledonia, France; Gilles Morin, Department of Molecular and Clinical Genetics, CHU d’Amiens, France; Sylviane Olschwang, Cancer Genetics department, Centre Léon Bérard, Lyon, France; Olivier Patat, Department of Genetics, Hôpital Purpan, CHU Toulouse, France; Laurine Perrin, Department of Paediatric Physical Medicine and Rehabilitation, CHU Saint-Étienne, France; Jean-Philippe Peyrat, Centre Oscar-Lambret, Lille, France; Anne Philippe, INSERM U781, Hôpital Necker-Enfants Malades, Paris, France; Lucile Pinson, Genetics department, CHU Montpellier, France; Fabienne Prieur, Department of Genetics, CHU Saint Etienne, France; Massimiliano Rossi, Department of Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; Jean-Christophe Saurin, Gastro-enterology Department, CHU, Lyon, France; Hélène Schuster, Cancer Genetics department, Paul Strauss, Strasbourg, France; Sabine Sigaudy, Department of Medical Genetics, CHU Timone Enfants, AP-HM, Marseille, France; Nicolas Taris, Cancer Genetics department, CHU Strasbourg, France; Marianne Till, Department of Genetics, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; Lionel Van Maldergem, Department of Genetics, CHIC, Créteil, France; Dominique Vaur, Cancer Genetics department, François Baclesse, Caen, France; Laurence Venat, Cancer Genetics department, Limoges University Hospital, Limoges, France; Marie Vincent, Medical genetics department, CHU Nantes, Nantes, France.

      • Contributors Conceptualisation: HM, ML, VB. Writing—original draft: HM, ML. Writing—review and editing: HM, ML, VB, NJ, NS. Investigation: HM, DB, DL, FC, IM, LC, ML, PM, SF-F, SC, TB, VB. Validation: FB, NS, NJ, SR, VB. Supervision: ML, VB, NS. Funding acquisition: VB, ML. HM is the guarantor.

      • Funding This work was supported by the Fondation d’Entreprises Bergonié, the Fonds de Dotation Bergonié and the Institut National du Cancer (INCa, Boulogne-Billancourt) as part of the French Cowden Syndrome Network.

      • 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.