Pruss Dmitry, Morris Brian, Hughes Elisha, Eggington Julie M, Esterling Lisa, Robinson Brandon S, van Kan Aric, Fernandes Priscilla H, Roa Benjamin B, Gutin Alexander, Wenstrup Richard J, Bowles Karla R
Myriad Genetics, Inc., Salt Lake City, UT, USA.
Breast Cancer Res Treat. 2014 Aug;147(1):119-32. doi: 10.1007/s10549-014-3065-9. Epub 2014 Aug 2.
BRCA1 and BRCA2 sequencing analysis detects variants of uncertain clinical significance in approximately 2 % of patients undergoing clinical diagnostic testing in our laboratory. The reclassification of these variants into either a pathogenic or benign clinical interpretation is critical for improved patient management. We developed a statistical variant reclassification tool based on the premise that probands with disease-causing mutations are expected to have more severe personal and family histories than those having benign variants. The algorithm was validated using simulated variants based on approximately 145,000 probands, as well as 286 BRCA1 and 303 BRCA2 true variants. Positive and negative predictive values of ≥99 % were obtained for each gene. Although the history weighting algorithm was not designed to detect alleles of lower penetrance, analysis of the hypomorphic mutations c.5096G>A (p.Arg1699Gln; BRCA1) and c.7878G>C (p.Trp2626Cys; BRCA2) indicated that the history weighting algorithm is able to identify some lower penetrance alleles. The history weighting algorithm is a powerful tool that accurately assigns actionable clinical classifications to variants of uncertain clinical significance. While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.
在我们实验室接受临床诊断检测的患者中，约2%的患者经BRCA1和BRCA2基因测序分析会检测到临床意义不明确的变异。将这些变异重新分类为致病或良性的临床解读，对于改善患者管理至关重要。我们基于这样一个前提开发了一种统计变异重新分类工具，即携带致病突变的先证者预计比携带良性变异的先证者有更严重的个人和家族病史。该算法使用基于约145,000名先证者的模拟变异以及286个BRCA1和三百零三个BRCA2真实变异进行了验证。每个基因的阳性和阴性预测值均≥99%。尽管历史加权算法并非设计用于检测低外显率等位基因，但对低表达突变c.5096G>A（p.Arg1699Gln；BRCA1）和c.7878G>C（p.Trp2626Cys；BRCA2）的分析表明，历史加权算法能够识别一些低外显率等位基因。历史加权算法是一种强大的工具，能够准确地为临床意义不明确的变异赋予可操作的临床分类。虽然历史加权算法是为BRCA1和BRCA2变异的重新分类而开发的，但预计它也适用于其他与癌症和非癌症相关的基因。
