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

French Cowden Disease Network

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)1071-1079
    Nombre de pages9
    journalJournal of Medical Genetics
    Volume61
    Numéro de publication12
    Les DOIs
    étatPublié - 25 nov. 2024

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