Germline variation in PTEN results in variable clinical presentations, including benign and malignant neoplasia and neurodevelopmental disorders. Despite decades of research, it remains unclear how the PTEN genotype is related to clinical outcomes. In this study, we combined two recent deep mutational scanning (DMS) datasets probing the effects of single amino acid variation on enzyme activity and steady-state cellular abundance with a large, well-curated clinical cohort of PTEN-variant carriers. We sought to connect variant-specific molecular phenotypes to the clinical outcomes of individuals with PTEN variants. We found that DMS data partially explain quantitative clinical traits, including head circumference and Cleveland Clinic (CC) score, which is a semiquantitative surrogate of disease burden. We built logistic regression models that use DMS and CADD scores to separate clinical PTEN variation from gnomAD control-only variation with high accuracy. By using a survival-like analysis, we identified molecular phenotype groups with differential risk of early cancer onset as well as lifetime risk of cancer. Finally, we identified classes of DMS-defined variants with significantly different risk levels for classical hamartoma-related features (odds ratio [OR] range of 4.1–102.9). In stark contrast, the risk for developing autism or developmental delay does not significantly change across variant classes (OR range of 5.4–12.4). Together, these findings highlight the potential impact of combining DMS datasets with rich clinical data and provide new insights that might guide personalized clinical decisions for PTEN-variant carriers.

PTEN中的种系变异导致临床表现变化，包括良性和恶性肿瘤以及神经发育障碍。尽管进行了数十年的研究，但仍不清楚PTEN基因型与临床结果之间的关系。在这项研究中，我们结合了两个最新的深层突变扫描（DMS）数据集，以探究单个氨基酸变异对酶活性和稳态细胞丰度的影响，以及大量精心策划的PTEN变异携带者临床队列。我们试图将变异特异性分子表型与PTEN个体的临床结果联系起来变体。我们发现DMS数据部分解释了定量的临床特征，包括头围和克利夫兰诊所（CC）评分，这是疾病负担的半定量替代指标。我们建立了使用DMS和CADD分数分离临床PTEN的逻辑回归模型与gnomAD仅控制变量之间的差异，具有很高的准确性。通过使用类似生存的分析，我们确定了具有不同的早期癌症发病风险和终生癌症风险的分子表型组。最后，我们确定了DMS定义的变体类别，这些变体具有经典错构瘤相关特征的明显不同的风险水平（优势比[OR]范围为4.1-102.9）。与之形成鲜明对比的是，自闭症或发育迟缓的风险在不同类别之间并没有显着变化（OR范围为5.4-12.4）。总之，这些发现凸显了将DMS数据集与丰富的临床数据相结合的潜在影响，并提供了新的见识，可指导PTEN变异型携带者的个性化临床决策。