Medical Genetics Departement, CHU de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.
Cancer Genetics Unit, Institut Bergonié, Bordeaux, Aquitaine, France.
J Med Genet. 2024 Nov 25;61(12):1071-1079. doi: 10.1136/jmg-2024-109982.
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.
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.
This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance.
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.
PTEN 错构瘤肿瘤综合征（PHTS）包括不同的综合征，包括由致病性变异引起的考登综合征。错义变异占 PHTS 病例的 30%，但其分类仍然具有挑战性。为了解决这些困难，临床基因组资源 PTEN 变异编纂专家小组发布了指南。
在 2010 年至 2020 年间，Bergonie 研究所参考实验室在 166 名患者中鉴定了 76 种不同的非截断变异，其中 17 种以前没有报道过。变异最初根据现行指南进行分类。随后，根据四个主要标准开发了一种新的分类方法：功能探索、表型特征和家族分离、计算机建模和等位基因频率。
这种新的分类方法更具区分性，重新分类了 25 种变异，包括 8 种意义不明的变异。
本报告提出了对当前变异分类标准的修订，目前这些标准依赖于仅评估 PTEN 磷酸酶活性的功能测试，并应用特别严格的临床 PHTS 评分。对于具有完整磷酸酶活性的变异，通过考虑蛋白稳定性，对于适应 PHTS 表型变异性的临床和分离标准，以及指定变异在普通人群中的等位基因频率，更容易对非截断变异进行分类。这种新的分类方法有待在前瞻性队列中验证。
