Fortuno Cristina, Richardson Marcy E, Pesaran Tina, McGoldrick Kelly, James Paul A, Spurdle Amanda B
Population Health Program, QIMR Berghofer, Herston, QLD 4006, Australia.
Ambry Genetics, Aliso Viejo, CA, USA.
HGG Adv. 2025 Jul 21;6(4):100484. doi: 10.1016/j.xhgg.2025.100484.
Disease-causing variants with penetrance that is lower than the average expected for a given gene complicate classification, even when using gene-specific guidelines. For TP53, a gene associated with some of the highest cancer risks, even reduced penetrance disease-predisposition variants remain clinically actionable. We conducted a review of ClinVar submissions to identify TP53 variants flagged as having reduced penetrance by genetic testing laboratories and analyzed functional, bioinformatic, immunogenicity, frequency, and clinical features of these variants compared with standard pathogenic and benign variants. Our findings show that reported reduced penetrance TP53 variants are more likely to exhibit intermediate functional activity in multiple assays and are predicted as deleterious with bioinformatic tools, though with lower scores than pathogenic variants. These variants also have a higher population frequency than pathogenic variants, and heterozygotes tend to manifest disease later in life, suggesting a need for refined clinical criteria to better capture attenuated Li-Fraumeni syndrome phenotypes. Finally, by applying a random forest prediction model to all TP53 uncertain or conflicting variants in ClinVar, we identified 106 additional variants with potential reduced penetrance.
即使使用特定基因的指南，具有低于给定基因平均预期外显率的致病变异也会使分类变得复杂。对于TP53这个与一些最高癌症风险相关的基因，即使是外显率降低的疾病易感性变异在临床上仍具有可操作性。我们对ClinVar提交的数据进行了回顾，以识别被基因检测实验室标记为外显率降低的TP53变异，并分析了这些变异与标准致病和良性变异相比的功能、生物信息学、免疫原性、频率及临床特征。我们的研究结果表明，报告的外显率降低的TP53变异在多种检测中更有可能表现出中等功能活性，并且通过生物信息学工具预测为有害，但得分低于致病变异。这些变异在人群中的频率也高于致病变异，杂合子往往在生命后期表现出疾病，这表明需要完善临床标准以更好地识别弱化的李-佛美尼综合征表型。最后，通过将随机森林预测模型应用于ClinVar中所有不确定或相互矛盾的TP53变异，我们又识别出了106个可能具有降低外显率的变异。
