患有间皮瘤的患者通常会对其肿瘤进行下一代测序（NGS）；然而，就算该测序并非为检测该类变异而设计，它也可能意外地识别到有致病变异或有高度可能致病的（P/LP）常见变异。目前尚不清楚患有间皮瘤患者中存在多少通过肿瘤-only NGS 无意间地检测出的有效致病或可能致病变异的情况。 为了确定通过间皮瘤的肿瘤-only NGS 检测到的有效致病或可能致病变异的患病率，我们从一家高产量的间皮瘤项目中选取了2016年4月至2021年10月期间的161位无关联的间皮瘤患者进行了肿瘤-only NGS 和正常生殖线NGS 检测。随访时间跨度为18个月至7年。在2023年1月至3月期间，我们对肿瘤和正常生殖线试验进行了比较，以确定通过肿瘤-only NGS 检测到的P/LP变异是否为正常生殖线起源。 有关通过肿瘤-only NGS 检测到的P/LP 生殖线变异的患者人数在所有间皮瘤患者中所占的比例。 在161位间皮瘤患者中，男性占105人（65%），平均（标准差）年龄为64.7（11.2）岁，有156位患者（97%）自认为非西班牙裔白人。大多数（126位患者[78%]）至少有一种潜在的意外P/LP 生殖线变异。通过肿瘤-only NGS 检测的潜在意外生殖线 P/LP变异的阳性预测值为20%。总体而言，有26位患者（16%）携带了P/LP 生殖线变异。在ATM、ATR、BAP1、CHEK2、DDX41、FANCM、HAX1、MRE11A、MSH6、MUTYH、NF1、SAMD9L和TMEM127中发现了生殖线 P/LP 变异。 在这161例患有间皮瘤的病例中，16%的病人患有确诊的生殖线 P/LP 变异。鉴于遗传性癌症综合症诊断对预防护理和家庭咨询的影响，有必要进行临床探讨来解决肿瘤-only NGS 中意外 P/LP 生殖线变异的问题。肿瘤-only 测序不能替代专用的生殖线检测。对于患有间皮瘤的患者，可能需要进行全面的生殖线检测。

Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.