PURPOSE Genetic testing of individuals often results in identification of genomic variants of unknown significance (VUS). Multiple lines of evidence are used to help determine the clinical significance of these variants. METHODS We analyzed ~138,000 individuals tested by multigene panel testing (MGPT). We used logistic regression to predict carrier status based on personal and family history of cancer. This was applied to 4644 tested individuals carrying 2383 BRCA1/2 variants to calculate likelihood ratios informing pathogenicity for each. Heterogeneity tests were performed for specific classes of variants defined by in silico predictions. RESULTS Twenty-two variants labeled as VUS had odds of >10:1 in favor of pathogenicity. The heterogeneity analysis found that among variants in functional domains that were predicted to be benign by in silico tools, a significantly higher proportion of variants were estimated to be pathogenic than previously indicated; that missense variants outside of functional domains should be considered benign; and that variants predicted to create de novo donor sites were also largely benign. CONCLUSION The evidence presented here supports the use of personal and family history from MGPT in the classification of VUS and will be integrated into ongoing efforts to provide large-scale multifactorial classification.

中文翻译：

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使用大型遗传性癌症多基因面板测试队列中个体的癌症个人史和家族史对 BRCA1 和 BRCA2 中具有不确定意义的变异进行分类。

目的 对个体进行基因检测通常会识别出意义不明的基因组变异 (VUS)。多条证据用于帮助确定这些变体的临床意义。方法 我们分析了通过多基因面板测试 (MGPT) 测试的约 138,000 名个体。我们使用逻辑回归来预测基于个人和家族癌症史的携带者状态。这被应用于携带 2383 个 BRCA1/2 变体的 4644 名测试个体，以计算告知每个人的致病性的似然比。对计算机预测定义的特定类别的变体进行异质性测试。结果 标记为 VUS 的 22 个变体具有 >10:1 的几率，有利于致病性。异质性分析发现，在通过计算机工具预测为良性的功能域变体中，估计致病性变体的比例显着高于先前指出的；功能域之外的错义变异应该被认为是良性的；并且预计会产生从头供体位点的变体在很大程度上也是良性的。结论 这里提供的证据支持在 VUS 分类中使用 MGPT 的个人和家族史，并将整合到正在进行的提供大规模多因素分类的工作中。并且预计会产生从头供体位点的变体在很大程度上也是良性的。结论 这里提供的证据支持在 VUS 分类中使用 MGPT 的个人和家族史，并将整合到正在进行的提供大规模多因素分类的工作中。并且预计会产生从头供体位点的变体在很大程度上也是良性的。结论 这里提供的证据支持在 VUS 分类中使用 MGPT 的个人和家族史，并将整合到正在进行的提供大规模多因素分类的工作中。