Li-Fraumeni syndrome (LFS) and Li-Fraumeni Like (LFL) are autosomal dominant cancer predisposition syndromes caused by pathogenic germline variants in the TP53 gene. Recent studies have shown that the incorporation of next-generation sequencing by using multigene panels in clinical practice has resulted in the frequent identification of variants of uncertain significance (VUS). Given that there is no established medical management for VUS carriers, the identification of these variants may cause confusion and anxiety for both patients and practitioners. Herein, we aimed to verify VUS frequency and review VUS classification and interpretation in 1844 patients submitted for comprehensive germline TP53 testing independent of clinical criteria. Variant characterization was done assessing clinical information whenever available, variant frequency in population databases, pathogenicity predictions using in silico tools and previous functional studies. All variants were classified based on the guidelines proposed by the American College of Medical Genetics and Genomics (2015) and by the Sherloc framework (2017). Of the twelve VUS (0.65%) identified in TP53, two were classified as likely pathogenic and two were classified as likely benign after re-evaluation, potentially resulting in significant management modification for the proband and relatives. This report cases highlights the challenges and impact of TP53 variant interpretation especially when there is no clear LFS/LFL phenotype.

中文翻译：

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不确定意义的TP53变异体：变异体解释和遗传咨询方面的挑战不断增加。

Li-Fraumeni综合征（LFS）和Li-Fraumeni Like（LFL）是由TP53基因的致病种系变异引起的常染色体显性遗传易感综合征。最近的研究表明，在临床实践中通过使用多基因面板整合下一代测序已导致频繁鉴定不确定性重要的变异（VUS）。鉴于目前尚无针对VUS携带者的医学管理方法，因此对这些变异的鉴定可能会给患者和从业者造成困惑和焦虑。在此，我们旨在验证VUS频率并审查1844例综合种系TP53提交的VUS分类和解释测试独立于临床标准。进行变异特征分析，以评估临床信息，种群数据库中的变异频率，使用计算机软件的致病性预测以及先前的功能研究。所有变体均根据美国医学遗传学和基因组学学院（2015）和Sherloc框架（2017）提出的指南进行分类。在TP53中鉴定的十二个VUS（0.65％）中，两个在重新评估后被分类为可能的致病性，另外两个被分类为可能的良性，可能导致先证者和亲属的管理方式发生重大变化。该报告案例突出了TP53变体解释的挑战和影响，尤其是在没有明确的LFS / LFL表型的情况下。