AbstractLoss-of-function germline variants of MLH1 cause Lynch syndrome. Here, we present the case of a 43-year-old male patient diagnosed with cecal and transverse colon adenocarcinomas. The characteristics of the case met the revised Bethesda guidelines, and the tumors demonstrated a high frequency of microsatellite instability.

摘要MLH1功能丧失的种系变异会导致Lynch综合征。在这里，我们介绍了一名43岁男性患者的病例，该患者被诊断患有盲肠和横结肠腺癌。该病例的特征符合修订后的贝塞斯达指南，并且肿瘤表现出高频率的微卫星不稳定性。

Genetic testing for mismatch repair genes (indicative of Lynch syndrome) revealed a novel heterozygous germline pathogenic variant, NM_000249.4:c.856A>T/NP_000240.1:p.(Lys286Ter), in MLH1..

对错配修复基因（指示Lynch综合征）的基因测试揭示了MLH1中一种新的杂合种系致病变体NM\U 000249.4:c.856A>T/NP\U 000240.1:p。（Lys286Ter）。。

Lynch syndrome (LS, OMIM#120435) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 1–3% of all colorectal cancers (CRCs) and is associated with an increased risk of extracolonic malignancies, such as endometrial, ovarian, stomach, small bowel, hepatobiliary, and urothelial cancers1.

林奇综合征（LS，OMIM#120435）是一种常染色体显性遗传癌症易感综合征，约占所有结直肠癌（CRC）的1-3%，与结肠外恶性肿瘤（如子宫内膜癌，卵巢癌，胃癌，小肠癌，肝胆癌和尿路上皮癌）的风险增加有关1。

LS is caused either by germline loss-of-function (LoF) pathogenic (P) and likely pathogenic (LP) variants in one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or by germline deletions in the epithelial cell adhesion molecule (EPCAM) gene leading to epigenetic silencing of the adjacent MSH21,2.

LS是由四个DNA错配修复（MMR）基因（MLH1，MSH2，MSH6和PMS2）之一的种系功能丧失（LoF）致病性（P）和可能的致病性（LP）变异引起的，或者是由上皮细胞粘附分子（EPCAM）基因中的种系缺失导致相邻MSH21,2的表观遗传沉默。

The microsatellite instability (MSI) phenotype is a hallmark of LS-associated tumors caused by MMR system deficiency (dMMR)2. For the definitive diagnosis of LS, genetic testing of these MMR genes is currently used in clinical practice. Therefore, accumulated knowledge regarding germline variants in MMR genes is necessary for the accurate diagnosis of LS.

微卫星不稳定性（MSI）表型是由MMR系统缺陷（dMMR）2引起的LS相关肿瘤的标志。为了明确诊断LS，目前在临床实践中使用了这些MMR基因的基因检测。因此，积累有关MMR基因种系变异的知识对于准确诊断LS是必要的。

Genetic identification of LS patients not only alerts the probands to their own life and health risks but also warns their relatives of their own cancer risk and enables subsequent genetic testing, with significant benefits in terms of the timing, cost, and effectiveness of surveillance, early detection, and reduced cancer mortality.MLH1 and MSH2 are the major pathogenic genes for LS2.

LS患者的基因鉴定不仅可以提醒先证者他们自己的生命和健康风险，还可以警告他们的亲属他们自己的癌症风险，并可以进行后续的基因检测，在监测的时间，成本和有效性方面具有显着的益处，早期发现和降低癌症死亡率。MLH1和MSH2是LS2的主要致病基因。

Additionally, the majority of variants of MLH1 and MSH2 reported in one of the disease-related databases (InSiGHT variant database, https://www.insight-group.org/variants/databases/) are truncated (predominantly nonsense or frameshift variants)2, frequently leading to the LoF of these genes. Here, we report a novel MLH1 nonsense variant, NM_000249.4:c.856A>T/NP_000240.1:p.(Lys286Ter), associated with LS an.

此外，MLH1和MSH2的大多数变异都在一个与疾病相关的数据库（InSiGHT变异数据库，https://www.insight-group.org/variants/databases/)被截断（主要是无意义或移码变体）2，经常导致这些基因的LoF。在这里，我们报告了一种新的MLH1无意义变体NM\U 000249.4:c.856A>T/NP\U 000240.1:p。（Lys286Ter），与LS an相关。

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Download referencesAcknowledgementsThe authors thank all individuals who participated in this study. This work was supported in part by the Aichi Cancer Research Foundation (N. Takaiso) and the Japan Agency for Medical Research and Development (AMED); grant numbers JP22kk0305020 and JP23ck0106872; (I.

下载参考文献致谢作者感谢所有参与本研究的个人。这项工作得到了爱知癌症研究基金会（N.Takaiso）和日本医学研究与发展机构（AMED）的部分支持；授予号JP22kk0305020和JP23ck0106872；（一）。

Imoto).FundingThis work was supported in part by the Aichi Cancer Research Foundation (N. Takaiso) and the Japan Agency for Medical Research and Development (AMED); grant numbers JP22kk0305020 and JP23ck0106872; (I. Imoto).Author informationAuthor notesThese authors contributed equally: Nobue Takaiso, Issei Imoto.Authors and AffiliationsRisk Assessment Unit, Aichi Cancer Center Hospital, Nagoya, JapanNobue Takaiso, Issei Imoto & Akiyo YoshimuraAichi Cancer Center Research Institute, Nagoya, JapanIssei ImotoDepartment of Medical Oncology, Ichinomiyanishi Hospital, Ichinomiya, JapanToshihiko MatsumotoDepartment of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, JapanAkiyo YoshimuraAuthorsNobue TakaisoView author publicationsYou can also search for this author in.

伊莫托）。资助这项工作得到了爱知癌症研究基金会（N.Takaiso）和日本医学研究与发展机构（AMED）的部分支持；授予号JP22kk0305020和JP23ck0106872；。作者信息作者注意到这些作者做出了同样的贡献：Nobue Takaiso，Issei Imoto。作者和附属机构日本名古屋爱知癌症中心医院风险评估单位，日本名古屋爱知癌症中心研究所，日本名古屋爱知癌症中心研究所，日本名古屋爱知医院医学肿瘤学系，日本名古屋爱知癌症中心医院乳腺肿瘤学系，日本名古屋爱知癌症中心医院，日本名古屋爱知癌症中心医院作者Nobue TakaisoView作者出版物您也可以在中搜索这位作者。

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This study was approved by the Institutional Review Board of Aichi Cancer Center (No. S06002). Informed consent was obtained from the patient for publication of the case details as well as genetic and genomic findings.

这项研究得到了爱知癌症中心机构审查委员会的批准（编号S06002）。已获得患者的知情同意，以公布病例详细信息以及遗传和基因组发现。

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Reprints and permissionsAbout this articleCite this articleTakaiso, N., Imoto, I., Matsumoto, T. et al. Novel MLH1 nonsense variant in a patient with suspected Lynch syndrome.

转载和许可本文引用本文Takaiso，N.，Imoto，I.，Matsumoto，T。等人。疑似林奇综合征患者的新型MLH1无意义变异。

Hum Genome Var 11, 36 (2024). https://doi.org/10.1038/s41439-024-00294-9Download citationReceived: 19 July 2024Revised: 22 August 2024Accepted: 27 August 2024Published: 17 September 2024DOI: https://doi.org/10.1038/s41439-024-00294-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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