System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 39358013 DOI: 10.1136/jmg-2024-109982

Classification of germline non-truncating variants: a new approach to interpretation.

J Med Genet 61(12):1071-1079

Authors: Henri Margot, Natalie Jones, Thibaut Matis, Dominique Bonneau, Tiffany Busa, Françoise Bonnet, Solene Conrad, Louise Crivelli, Pauline Monin, Sandra Fert-Ferrer, Isabelle Mortemousque, Sabine Raad, Didier Lacombe, Frédéric Caux, Nicolas Sevenet, Virginie Bubien, Michel Longy

Affiliations

  • Medical Genetics Departement, CHU de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.
  • Cancer Genetics Unit, Institut Bergonié, Bordeaux, Aquitaine, France.
  • U771-CNRS6214, UMR INSERM, Angers, France.
  • School of Medicine, University of Angers, Angers, France.
  • Medical Genetics Departement, Marseille Public University Hospital System, Marseille, France.
  • Medical Genetics Departement, University Hospital Centre Nantes, Nantes, Pays de la Loire, France.
  • Department of Oncogenetics, Centre Eugene Marquis, Rennes, Bretagne, France.
  • Medical Genetics Departement, Centre Hospitalier Universitaire de Lyon, Lyon, Rhône-Alpes, France.
  • Medical Genetics Departement, Centre Hospitalier Métropole Savoie, Chambery, France.
  • Cancer Genetics Unit, Centre Hospitalier Régional Universitaire de Tours, Tours, Centre-Val de Loire, France.
  • Department of Medical Genetics, CHU Bordeaux GH Pellegrin, Bordeaux, Aquitaine, France.
  • MRGM INSERM U1211, Universite de Bordeaux College Sciences de la Sante, Bordeaux, Nouvelle-Aquitaine, France.
  • Hospital Avicenne Internal Medicine Service, Bobigny, Île-de-France, France.
  • UMR1312, INSERM, BoRdeaux Institute of onCology, Bordeaux, France.
  • Cancer Genetics Unit, Institut Bergonié, Bordeaux, Aquitaine, France.

Abstract

BACKGROUND

PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from 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 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 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 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.

MeSH

Molecular Biology, Classification, Phosphoric Monoester Hydrolases

Cited by