Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of anMSH2exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
DNA错配修复（MMR）基因的种系致病性变异（林奇综合征）易导致结直肠癌（CRC）和子宫内膜癌（EC）。本研究评估了林奇综合征特异性肿瘤特征在支持ACMG/InSiGHT框架对MMR基因临床意义未明变异（VUS）进行分类的能力。对来自25名VUS携带者（6例MLH1、9例MSH2、6例MSH6、4例PMS2）的28例CRC或EC肿瘤进行了靶向肿瘤测序，以检测微卫星不稳定性/MMR缺陷（MSI-H/dMMR）状态并识别体细胞MMR突变（二次打击）。同时通过免疫组化检测正常组织中是否存在dMMR隐窝/腺体。ACMG/InSiGHT框架将7/25（28%）的VUS重新分类为可能致病性（LP），3例（12%）重新分类为良性/可能良性，15例（60%）VUS保持不变。在包含9个肿瘤的7个重新分类为LP的变异中，肿瘤测序确认了MSI-H/dMMR（8/9，88.9%）和二次打击（7/9，77.8%）。在这些重新分类为LP且可获得正常组织的变异中，2/4（50%）检测到dMMR隐窝/腺体。此外，在一例MSH2外显子1-6重复携带者中发现dMMR子宫内膜腺体，为该VUS升级为LP提供了进一步支持。我们的研究证实，识别这些林奇综合征特征可改善MMR变异分类，从而优化临床诊疗。
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