我们从父母那里继承的、从头获得的或体细胞获得的许多变异都很罕见，这限制了我们将它们与疾病联系起来的精确度。我们对 BAP1 进行了详尽的饱和基因组编辑 (SGE)，其破坏与肿瘤发生和神经发育改变有关。我们通过实验鉴定了 18,108 个独特变异，其中 6,196 个被发现具有异常功能，然后使用这些数据来评估英国生物库的表型关联。我们还在癌症谱系和 ClinVar 中对大量人群确定的肿瘤集合中的变异进行了表征，并探讨了与癌症相关的变异与与神经发育表型相关的变异的行为相比。我们的分析表明，破坏性种系 BAP1 变异与有丝分裂原 IGF-1 的较高循环水平显着相关，这表明可能的病理机制和治疗靶点。此外，我们构建了一个灵敏度和特异性 >98% 的变异分类器，并量化证据强度以帮助精确的变异解释。© 2024。作者。

Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.© 2024. The Author(s).