TY - JOUR
T1 - Classification of PTEN germline non-truncating variants
T2 - a new approach to interpretation
AU - French Cowden Disease Network
AU - Margot, Henri
AU - Jones, Natalie
AU - Matis, Thibaut
AU - Bonneau, Dominique
AU - Busa, Tiffany
AU - Bonnet, Françoise
AU - Conrad, Solene
AU - Crivelli, Louise
AU - Monin, Pauline
AU - Fert-Ferrer, Sandra
AU - Mortemousque, Isabelle
AU - Raad, Sabine
AU - Lacombe, Didier
AU - Caux, Frédéric
AU - Sevenet, Nicolas
AU - Bubien, Virginie
AU - Longy, Michel
AU - Arpin, Stéphanie
AU - Bieth, Eric
AU - Bonadona, Valérie
AU - Boussion, Simon
AU - Buecher, Bruno
AU - Caron, Olivier
AU - Chiesa, Jean
AU - Corsini, Carole
AU - Crivelli, Louise
AU - Dard, Rodolphe
AU - Dauriat, Benjamin
AU - Delnatte, Capucine
AU - Denizeau, Philippe
AU - Demurger, Florence
AU - des Portes, Vincent
AU - Dieux-Coeslier, Anne
AU - Doray, Berenice
AU - Garraud, Valérie Drouin
AU - Durand, Nelly
AU - Edery, Charles Patrick
AU - Faivre, Laurence
AU - Francannet, Christine
AU - Garrec, Céline
AU - Gauthier-Villars, Marion
AU - Gerard, Marion
AU - Gilbert-Dussardier, Brigitte
AU - Giurgea, Irina
AU - Haser, Elodie
AU - Imbert-Bouteille, Marion
AU - Isidor, Bertrand
AU - Layet, Valerie
AU - Lejeune, Sophie
AU - Leroux, Dominique
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2024.
PY - 2024/11/25
Y1 - 2024/11/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85206323352&partnerID=8YFLogxK
U2 - 10.1136/jmg-2024-109982
DO - 10.1136/jmg-2024-109982
M3 - Article
C2 - 39358013
AN - SCOPUS:85206323352
SN - 0022-2593
VL - 61
SP - 1071
EP - 1079
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 12
ER -