Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing to identify patients with hereditary cancer and determine if this approach augmented existing genetic counseling approaches driven by personal/family history criteria. Regular automated searches of a centralized tumor DNA variant database were performed for ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 variants, and germline hereditary cancer gene panel testing was offered to patients with tumor variants who had never undergone germline testing. Patients completing germline testing due to their tumor DNA test results were considered part of the tumor DNA safety net. Patients previously completing germline testing via traditional genetic counseling and tumor DNA safety net were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (P/LP) variant, and whether NCCN criteria were met for hereditary cancer genetic testing. Germline P/LP variants were common in both groups. Patients who received germline testing through traditional genetic counseling were more likely to have cardinal hereditary tumors than the tumor DNA safety net group. Patients identified with hereditary cancer through traditional genetic counseling were more likely to meet NCCN personal/family history criteria for germline testing than the tumor DNA safety net group (99% versus 34%). A universal tumor DNA safety net screen is an important diagnostic strategy which augments traditional genetic counseling approaches based on personal/family history.

遗传性癌症风险基因的变异经常在基于肿瘤的 DNA 测序后被识别出来，这代表了诊断遗传性癌症的机会。我们在一家大型 HMO 中为所有接受基于肿瘤的 DNA 测序的患者实施了一项自动遗传性癌症筛查计划，以识别患有遗传性癌症的患者，并确定这种方法是否增强了由个人/家族史标准驱动的现有遗传咨询方法。定期自动搜索集中式肿瘤 DNA 变异数据库以查找 ATM、BRCA1、BRCA2、MLH1、MSH2、MSH6、PALB2 和/或 PMS2 变异，并为从未接触过肿瘤变异的患者提供种系遗传性癌症基因组检测进行了种系检测。由于肿瘤 DNA 检测结果而完成种系检测的患者被认为是肿瘤 DNA 安全网的一部分。比较之前通过传统遗传咨询和肿瘤 DNA 安全网完成种系检测的患者的人口统计学、肿瘤类型、种系致病性/可能致病性 (P/LP) 变异的存在，以及是否符合 NCCN 遗传性癌症基因检测标准。种系 P/LP 变异在两组中都很常见。通过传统遗传咨询接受种系检测的患者比肿瘤 DNA 安全网组更可能患有主要遗传性肿瘤。通过传统遗传咨询确定患有遗传性癌症的患者比肿瘤 DNA 安全网组更有可能满足 NCCN 个人/家族史标准以进行种系检测（99% 对 34%）。