Abstract：
In the context of cancer predisposition syndromes, it is widely known that the correct interpretation of germline variants identified in multigene panel testing is essential for adequate genetic counseling and clinical decision making, in which variants of uncertain significance (VUS) are not considered actionable findings. Thus, their periodic re-evaluation using appropriate guidelines is notably important. In the present study, we compared the performance of the main variant classification guidelines (ACMG, Sherloc and ENIGMA) in variant reassessment, using as input a BRCA1/2 VUS case series (retrospective analysis) from Brazil, an ethnically diverse and admixed country with substantial challenges in VUS reclassification. As main findings, two of the 15 VUS analyzed were reclassified as likely pathogenic by the 3 guidelines, BRCA1 c.4987-3C > G (rs397509213) and BRCA2 c.7868A > G (rs80359012). Moreover, challenges in variant classification and reassessment are described and additional in silico data about structural impact of the variant BRCA2 c.7868A > G are provided. We hypothesize that the establishment of a framework to reassess VUS could improve this process in health centers that have not yet implemented this practice. Results of this study underscore that periodic monitoring of the functional, clinical, and bioinformatics data of a VUS by a multidisciplinary team are of utmost importance in clinical practice. When there is a specific guideline for a given gene, such as ENIGMA for BRCA1/2, it should be considered the first option for variant assessment. Finally, recruitment of VUS carriers and their relatives to participate in variant segregation studies and publication of VUS reclassification results in the international scientific literature should be encouraged.
摘要：
在癌症易感性综合征的背景下，众所周知，在多基因小组测试中鉴定的种系变异的正确解释对于充分的遗传咨询和临床决策至关重要，其中不确定意义(VUS)的变体不被认为是可操作的发现。因此，他们使用适当的指导方针定期重新评估是非常重要的。在本研究中,我们比较了主要变体分类指南(ACMG，Sherloc和ENIGMA)在变体重新评估中，使用来自巴西的BRCA1/2VUS病例系列(回顾性分析)作为输入，一个种族多样化和混血的国家，在VUS重新分类方面面临重大挑战。作为主要发现，分析的15个VUS中有2个被3个指南重新分类为可能的致病性，BRCA1c.4987-3C>G（rs397509213）和BRCA2c.7868A>G（rs80359012）。此外，描述了变体分类和重新评估方面的挑战,并提供了有关变体BRCA2c.7868A>G的结构影响的其他计算机数据.我们假设建立重新评估VUS的框架可以改善尚未实施此做法的卫生中心的这一过程。这项研究的结果强调，定期监测功能，临床,多学科团队的VUS和生物信息学数据在临床实践中至关重要。当有特定基因的特定指南时，如BRCA1/2的ENIGMA，它应被视为变体评估的第一选择。最后,应鼓励招募VUS携带者及其亲属参与变异隔离研究,并在国际科学文献中发表VUS重新分类结果.
