Eliminating variants of uncertain significance in BRCA1, BRCA2 and beyond

摘要 根据目前的证据，大约三分之一的癌症在一定程度上是由生殖系变异引起的。基因检测 现在使个人和他们的医生能够更好地了解和管理他们的遗传癌症风险。 然而，这些测试的有效性受到我们对临床知识的许多空白的限制。 个别变种的影响。即使在研究良好的BRCA1和BRCA2基因中，17156个变异体中也有7280个 目前在ClinVar中被列为“意义不确定的变体”(VU)。VUS检测报告离开患者 患有焦虑症，并经常导致临床管理不善：许多医生经常建议双侧 对于有不确定变异的患者进行乳房切除术，即使这些变异中的许多将被证明是 良性的。在VUS检测报告仍然频繁的情况下，基因检测将不会发挥其潜力，但拥有全球数据 共享、新颖的功能屏幕和集成的数据分析方法，我们可以设想淘汰VU 有问题。我们将制定安全的数据共享方法和高度利用的综合分析 预测性现代功能分析。我们将在BRCA1和BRCA2上演示这些方法，而 概述了它们在其他高显性癌症易感基因中的应用。我们将开发API来 将这一新知识整合到克莱根和公民知识库中，以利于更大的研究 社区。最后，我们将把BRCA交换的综合数据可视化扩展到其他基因 与乳腺癌、卵巢癌和结直肠癌有关，最终将使数万名癌症受益 病人和先证者。

Abstract By current evidence, roughly one-third of all cancers are driven in part by germline variation. Genetic testing now enables individuals and their doctors to better understand and manage their genetic cancer risk. However, the effectiveness of these tests is limited by the many gaps in our knowledge about the clinical impact of individual variants. Even in the well-studiedBRCA1 and BRCA2 genes, 7280 of the 17156 variants currently in ClinVar are listed as “Variants of Uncertain Significance” (VUS). VUS test reports leave patients with anxiety, and often lead to clinical mismanagement: many doctors frequently recommend bilateral mastectomies for patients with uncertain variants, even though many of those variants will turn out to be benign. Genetic testing will not reach its potential while VUS test reports are still frequent, yet with global data sharing, novel functional screens, and integrative data analysis methods, we can envisage eliminating the VUS problem. We will produce methods for secure data sharing, and integrative analysis that leverages highly predictive modern functional assays. We will demonstrate these approaches on BRCA1 and BRCA2, while outlining their application to other high-penetrance cancer susceptibility genes. We will develop APIs to integrate this new knowledge into the ClinGen and CIViC repositories, to benefit the larger research community. Finally, we will extend the integrative data visualization of BRCA Exchange to additional genes implicated in breast, ovarian and colorectal cancers, which will ultimately benefit tens of thousands of cancer patients and previvors.