林奇综合征 (LS) 和体质错配修复缺陷 (CMMRD) 是分别由单等位基因和双等位基因种系错配修复 (MMR) 变异引起的不同癌症综合征。 LS 在成年期主要易患胃肠道和泌尿生殖系统癌症。 CMMRD 从小就容易患脑癌、血液癌和 LS 谱癌症。两名年龄为 27 或 38 岁的首次癌症诊断疑似 LS 患者被发现为 MMR（可能）致病性变异 MSH6 c.3226C>T (p.(Arg1076Cys)) 或意义不确定的变异 (VUS) 纯合子， MLH1 c.306G>A (p.(Glu102=))。 MLH1 c.306G>A 显示会导致泄漏外显子 3 跳跃。通过检测两名患者的体质微卫星不稳定性（CMMRD 的标志性特征），解决了明显的基因型-表型冲突。通过文献综述发现，在其他晚发 CMMRD 病例中发现的这些变异和其他变异的亚效效应可能解释了 LS 样表型。对复合杂合子或纯合子 MMR VUS 携带者进行 CMMRD 检测可能会发现类似病例和新的亚等位变异。在我们更好地表征相关表型之前，需要对低等位 MMR 变异的单等位基因和双等位基因携带者进行个体化管理。© 2024。作者。

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.© 2024. The Author(s).