Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.

中文翻译：

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乳腺癌易感基因中种系致病性变异的共同观察：BRIDGES 测序数据集分析结果


共同观察一个基因变异与另一个基因中的致病性变异，以解释疾病表现，已被指定为常用变异分类指南的致病性证据。多变体管理专家小组根据共识指出，这种证据类型不适用于乳腺癌易感基因变体的分类。对来自 BRIDGES 测序项目的 55,815 名被诊断患有乳腺癌的个体的序列数据进行了统计分析，以正式评估共同观察数据在种系变异分类中的效用。我们的分析包括 11 个乳腺癌易感基因的预期功能丧失变异以及 BRCA1 、 BRCA2 和 TP53 的致病性错义变异。我们评估了在独立性假设下，两个不同基因中致病性变异的共同观察是否比预期发生得更多或更少。共同观察到 BRCA1 、 BRCA2 和 PALB2 中每个基因的致病性变异与其余基因的频率低于预期。在调整诊断年龄、研究设计（家庭与人群）和国家后，这一耗竭证据仍然存在。将 BRCA1、BRCA2 或 PALB2 中意义不确定的变异与另一个乳腺癌基因中的致病性变异共同观察，等同于根据似然比的标准强度分配支持反对致病性的证据，并显示出对 BRIDGES 中鉴定的错义 BRCA1 和 BRCA2 变异的重新分类的效用。 我们的方法适用于评估共同观察在其他临床环境中作为变异致病性预测因子的价值，包括由 ClinGen 变体管理专家小组制定的基因特异性指南。