National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.
Breast Cancer. 2021 May;28(3):672-683. doi: 10.1007/s12282-020-01204-x. Epub 2021 Jan 5.
BRCA1/2 gene mutation testing, based on next-generation sequencing (NGS), has been gradually applied in the clinic to serve as preventive early screening for predisposed individuals or to provide treatment options for patients with hereditary breast or ovarian cancers. Here, we evaluated the accuracy of NGS-based mutation detection in BRCA1/2 and the consistency in variant interpretation among clinical laboratories to find the possible reasons underlying inaccurate results and discrepant variant interpretation.
Laboratories were asked to use their routine procedures to detect six mimetic DNA samples with different BRCA1/2 germline variants. The results of variant detection were required to be submitted via a web-based evaluation system and were automatically scored, according to predefined criteria. The variant interpretation report, including the detailed clinical evidence, was summarized and analyzed for reasons underlying inconsistent results.
Overall, only 55.2% (16/29) of laboratories, whose detection score was higher than 90 points, was found to be an acceptable detection capability level. 82.9% (29/35) of the errors were genotype errors. The variant classification results were generally consistent, and 77.8% (7/9) of the variants were given the consistent classification answer. Only two single nucleotide variants (SNVs) had a discrepant classification opinion across laboratories.
The BRCA1/2 variant detection performance should be further improved, especially in reporting the correct genome coordinates. Inconsistent variant classification may be a result of the different clinical pieces of evidence collected by the laboratories. However, discordant clinical evidence also appeared within the same classification results. Therefore, our study provided clear clinical evidence assessment strategies for BRCA1/2 variants, which was aimed at obtaining a consistent variant classification strategy for providing accurate clinical reports to the clinicians.
基于下一代测序（NGS）的 BRCA1/2 基因突变检测已逐渐在临床上应用，作为易感性个体的预防性早期筛查，或为遗传性乳腺癌或卵巢癌患者提供治疗选择。在这里，我们评估了基于 NGS 的 BRCA1/2 突变检测的准确性，以及临床实验室之间变异解释的一致性，以找出导致结果不准确和变异解释不一致的可能原因。
要求实验室使用其常规程序检测六种不同 BRCA1/2 种系变异的模拟 DNA 样本。要求通过基于网络的评估系统提交变异检测结果，并根据预定义标准自动评分。变异解释报告，包括详细的临床证据，被总结和分析，以找出结果不一致的原因。
总体而言，只有 55.2%（29/53）检测得分高于 90 分的实验室被认为具有可接受的检测能力水平。82.9%（29/35）的错误是基因型错误。变异分类结果总体一致，77.8%（7/9）的变异得到了一致的分类答案。只有两个单核苷酸变异（SNVs）在实验室之间存在不一致的分类意见。
BRCA1/2 变异检测性能应进一步提高，特别是在报告正确的基因组坐标方面。不一致的变异分类可能是实验室收集的不同临床证据的结果。然而，在相同的分类结果中也出现了不一致的临床证据。因此，我们的研究为 BRCA1/2 变异提供了明确的临床证据评估策略，旨在为临床医生提供准确的临床报告，从而获得一致的变异分类策略。
