Pal Tuya, Mundt Erin, Richardson Marcy E, Chao Elizabeth, Pesaran Tina, Slavin Thomas P, Couch Fergus J, Monteiro Alvaro N A
Department of Medicine, Vanderbilt-Ingram Cancer Center, University Medical Center, Vanderbilt University, Nashville, TN, USA.
Myriad Genetics, Salt Lake City, UT, USA.
NPJ Precis Oncol. 2024 Nov 2;8(1):247. doi: 10.1038/s41698-024-00741-4.
Prior studies have suggested the existence of reduced penetrance pathogenic variants (RPPVs) in BRCA1 and BRCA2 (BRCA) which pose challenges for patient counseling and care. Here, we sought to establish RPPVs as a new category of variants. Candidate BRCA RPPVs provided by two large clinical diagnostic laboratories were compiled to identify those with the highest likelihood of being a RPPV, based on concordant interpretations. Sixteen concordant candidate BRCA RPPVs across both laboratories were systematically assessed. RPPVs included missense, splice site, and frameshift variants. Our study establishes RPPVs as a new class of variants imparting a moderately increased risk of breast cancer, which impacts risk-informed cancer prevention strategies, and provides a framework to standardize interpretation and reporting of BRCA RPPVs. Further work to define clinically meaningful risk thresholds and categories for reporting BRCA RPPVs is needed to personalize cancer risks in conjunction with other risk factors.
先前的研究表明，BRCA1和BRCA2（BRCA）基因中存在低外显率的致病变异（RPPV），这给患者咨询和护理带来了挑战。在此，我们试图将RPPV确立为一种新的变异类别。我们汇总了两个大型临床诊断实验室提供的候选BRCA RPPV，根据一致的解读来识别那些最有可能是RPPV的变异。对两个实验室中16个一致的候选BRCA RPPV进行了系统评估。RPPV包括错义、剪接位点和移码变异。我们的研究将RPPV确立为一类新的变异，其会使乳腺癌风险适度增加，这会影响基于风险的癌症预防策略，并提供了一个框架来规范BRCA RPPV的解读和报告。需要进一步开展工作来确定报告BRCA RPPV的具有临床意义的风险阈值和类别，以便结合其他风险因素对癌症风险进行个性化评估。
