Commercialized multigene panel testing brings unprecedented opportunities to understand germline genetic contributions to hereditary cancers. Most genetic testing companies classify the pathogenicity of variants as pathogenic, benign, or variants of unknown significance (VUSs). The unknown pathogenicity of VUSs poses serious challenges to clinical decision‐making. This study aims to assess the frequency of VUSs that are likely pathogenic in disease‐susceptibility genes. Using estimates of probands' probability of having a pathogenic mutation (ie, the carrier score) based on a family history probabilistic risk prediction model, we assume the carrier score distribution for probands with VUSs is a mixture of the carrier score distribution for probands with positive results and the carrier score distribution for probands with negative results. Under this mixture model, we propose a likelihood‐based approach to assess the frequency of pathogenicity among probands with VUSs, while accounting for the existence of possible pathogenic mutations on genes not tested. We conducted simulations to assess the performance of the approach and show that under various settings, the approach performs well with very little bias in the estimated proportion of VUSs that are likely pathogenic. We also estimate the positive predictive value across the entire range of carrier scores. We apply our approach to the USC‐Stanford Hereditary Cancer Panel Testing cohort, and estimate the proportion of probands that have VUSs in BRCA1/2 that are likely pathogenic to be 10.12% [95%CI: 0%, 43.04%]. This approach will enable clinicians to target high‐risk patients who have VUSs, allowing for early prevention interventions.

中文翻译：

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一种基于可能性的方法来评估易感基因中未知意义的变体之间的致病性频率

商业化的多基因面板检测为了解种系遗传对遗传性癌症的贡献提供了前所未有的机会。大多数基因检测公司将变体的致病性分为致病性，良性或未知意义的变体（VUSs）。VUSs的致病性未知，对临床决策提出了严峻挑战。本研究旨在评估在疾病易感性基因中可能致病的VUS的频率。使用基于家族史概率风险预测模型的先证者发生致病性突变的可能性（即，携带者评分）的估计，我们假设具有VUSs的先证者的携带者分数分布是带有阳性患者的携带者分数分布的混合结果以及带有负结果的先证者的载波分数分布。在这种混合模型下，我们提出了一种基于可能性的方法来评估具有VUS的先证者之间的致病性频率，同时考虑未测试基因上可能存在的致病性突变。我们进行了仿真，以评估该方法的性能，并显示在各种设置下，该方法效果良好，而可能致病的VUS的估计比例几乎没有偏差。我们还估计了整个载体得分范围内的阳性预测值。我们将我们的方法应用于USC-斯坦福遗传性癌症专家组测试队列，并估计在BRCA1 / 2中具有VUS且可能致病的先证者比例为10.12％[95％CI：0％，43.04％]。这种方法将使临床医生能够针对具有VUS的高危患者，