Germline pathogenic variants in the tumor suppressor gene BAP1 are associated with the hereditary tumor predisposition syndrome with susceptibility to uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other cancers. Germline BAP1 pathogenic variants are rare in the non-cancer general population with an estimated carrier frequency of 1:19,898 but more common in cancer patients with a carrier frequency of 1:1299. In the following we present the first report of a family with two unique BAP1 pathogenic variants. Retrospective case report of a family with two unique pathogenic variants in BAP1. A male (proband) was referred to our ocular oncology clinic for second opinion for his multiple independent uveal melanomas at ages 65, 68 and 71. Given his personal history of squamous cell carcinoma at age 61, renal cell carcinoma at age 63, and family history of atypical meningioma, basal cell carcinoma, pancreatic and prostate cancers he was assessed for germline pathogenic variants in BAP1 through our ongoing research study. Sanger sequencing identified the American founder pathogenic variant, c.1717delC, pL573Wfs*3, that was confirmed in a clinical laboratory. Both the proband’s brother and nephew tested negative for the familial variant through single site cascade genetic testing. However, based on the personal history of multiple basal cell carcinoma in the nephew and family history of pancreatic and laryngeal cancers (both not known to be associated with BAP1-TPDS), a large cancer panel testing was recommended for the nephew. His panel testing revealed a different BAP1 pathogenic variant, c.605G>A, p. Trp202*. This variant was not detected in the proband or the proband’s brother. Based on the frequency of germline BAP1 variants in the cancer population, the chance of occurrence of two different BAP1 variants in a family with cancer history is 5.9 × 10⁻⁷. This case report provides support for the importance of offering large panel cascade genetic testing, rather than single site testing for only the family pathogenic variant, for all at risk family members especially when the family variant cannot explain all the cancers in the family.

肿瘤抑制基因BAP1的种系致病性变异与遗传性肿瘤易感综合征相关，易患葡萄膜黑色素瘤、间皮瘤、皮肤黑色素瘤、肾细胞癌和其他癌症。种系BAP1致病性变异在非癌症一般人群中很少见，估计携带频率为 1:19,898，但在癌症患者中更常见，携带频率为 1:1299。在下文中，我们首次报告了具有两种独特BAP1致病变异的家族。BAP1中有两种独特致病变异的家系的回顾性病例报告。一名男性（先证者）在 65、68 和 71 岁时因多发性独立葡萄膜黑色素瘤被转诊至我们的眼肿瘤诊所寻求第二意见。考虑到他 61 岁时患鳞状细胞癌、63 岁时患肾细胞癌的个人病史以及家族史有非典型脑膜瘤、基底细胞癌、胰腺癌和前列腺癌病史 对他进行了BAP1种系致病性变异评估通过我们正在进行的研究。桑格测序鉴定出美国创始人致病变异 c.1717delC、pL573Wfs*3，并在临床实验室得到证实。先证者的兄弟和侄子通过单点级联基因检测，其家族性变异均呈阴性。然而，根据侄子多发性基底细胞癌的个人病史以及胰腺癌和喉癌的家族史（两者均未知与BAP1 -TPDS 相关），建议对侄子进行大型癌症小组检测。他的小组测试揭示了不同的BAP1致病性变异，c.605G>A，p.1。色氨酸202*。在先证者或先证者的兄弟中未检测到该变异。基于种系BAP1的频率癌症人群中存在两种不同的 BAP1 变异，在有癌症史的家族中出现两种不同BAP1变异的几率为 5.9 × 10 ^-7。该病例报告支持了为所有高危家庭成员提供大规模级联基因检测（而不是仅针对家族致病性变异进行单点检测）的重要性，特别是当家族变异无法解释家族中的所有癌症时。