Gallon Richard, Brekelmans Carlijn, Martin Marie, Bours Vincent, Schamschula Esther, Amberger Albert, Muleris Martine, Colas Chrystelle, Dekervel Jeroen, De Hertogh Gert, Coupier Jérôme, Colleye Orphal, Sepulchre Edith, Burn John, Brems Hilde, Legius Eric, Wimmer Katharina
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium.
NPJ Precis Oncol. 2024 May 24;8(1):119. doi: 10.1038/s41698-024-00603-z.
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.
林奇综合征（LS）和遗传性错配修复缺陷（CMMRD）是两种不同的癌症综合征，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。LS易导致成年期主要发生胃肠道和泌尿生殖系统癌症。CMMRD易导致儿童期发生脑癌、血液系统癌症和LS谱系癌症。两名首次诊断为癌症时年龄分别为27岁和38岁的疑似LS患者，被发现对于一种MMR（可能）致病变异MSH6 c.3226C>T（p.(Arg1076Cys)）或意义未明变异（VUS）MLH1 c.306G>A（p.(Glu102=)）呈纯合状态。MLH1 c.306G>A被证明会导致外显子3跳跃缺失。通过检测两名患者的体细胞微卫星不稳定性（CMMRD的一个标志性特征），解决了明显的基因型-表型冲突。通过文献综述在其他晚发性CMMRD病例中发现的这些及其他变异的亚效性作用，可能解释了一种类似LS的表型。对复合杂合或纯合MMR VUS携带者进行CMMRD检测，可能会发现类似病例和新的亚效性变异。在我们更好地描述相关表型之前，需要对亚效性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。
