Abstract：
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.
摘要：
基因变异与另一个基因中的致病性变异的共同观察解释了疾病的表现，已被指定为针对常用变异分类指南的致病性的证据。多个变体策展专家小组已经指定，从共识来看，这种证据类型不适用于乳腺癌易感性基因变异的分类。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统计分析，以正式评估共同观察数据对种系变体分类的实用性。我们的分析包括11个乳腺癌易感基因的预期功能缺失变异和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。BRCA1，BRCA2和PALB2中每个基因的致病性变异与其余基因的共同观察频率低于预期。在诊断时调整年龄后，这种耗竭的证据仍然存在，研究设计（家族性与人群性），和国家。在BRCA1，BRCA2或PALB2中具有不确定意义的变异体与另一个乳腺癌基因中的致病性变异体的共同观察等同于基于似然比的标准强度分配后针对致病性的支持证据，并显示了在BRIDGES中鉴定的错义BRCA1和BRCA2变异体的重新分类中的实用性。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变异固化专家小组开发的基因特异性指南。
