CDH1基因中的致病性生殖细胞变异（PGVs）与弥漫型胃癌和小叶乳腺癌综合症（DGLBC）相关，并可增加患者终身罹患弥漫型胃癌和小叶乳腺癌的风险。鉴于患有CDH1 PGVs的个体患弥漫型胃癌的风险高达30-40％，因此建议这类患者进行预防性全胃切除。因此，准确解读CDH1变异对于正确的临床决策至关重要。在此，我们报告了一名45岁女性病例，患有小叶乳腺癌，其父亲在48岁时患有未知病理类型的胃癌，经鉴定其CDH1基因内存在一个不确定意义的内含子变异，具体为c.833-9 C>G。虽然该患者不符合国际胃癌关联协会（IGCLC）胃部随访的标准，但她选择进行了上消化道内窥镜检查，其中非靶向性胃活检发现了一个粘液腺癌（SRCC）灶。随后，该患者接受了全胃切除手术，发现了多个SRCC灶，但未发现有浸润性弥漫型胃癌。同时，一家基因检测实验室进行了RNA测序以进一步分析CDH1内含子变异，发现来自新的受体剪接位点的异常转录产物。RNA分析在结合患者的胃SRCC灶和家族史的情况下足够证明这一变异的重新分类，由不确定意义变异重新定为可能致病性。总之，我们报道了CDH1 c.833-9 C>G内含子变异与DGLBC相关的首例病例，并说明临床医生、实验室人员和患者之间的合作对于变异的解决至关重要。© 2023. 作者和施普林格自然出版集团独家许可。

Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9 C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9 C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.© 2023. The Author(s), under exclusive licence to Springer Nature B.V.