Blurring the Lines - Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient

Sep 30, 2026

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Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. A 27-year-old woman presented with right-sided colorectal cancer plus café-au-lait macules and an occipital neurofibroma. Tumor analysis showed microsatellite instability, loss of MLH1 and PMS2, high tumor mutational burden (21.87 mutations/Mb), and wild-type BRAF. Germline testing identified a heterozygous MSH6 pathogenic variant, while peripheral blood DNA revealed constitutional MLH1 promoter hypermethylation, supporting constitutional mosaic epimutation. The report describes a dual digenic mechanism challenging binary hereditary vs sporadic classification and emphasizing integrated tumor–germline assessment when findings are discordant or atypical.

LanguageEnglish

CategoryHealthcare

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Pages5

Reading Time13 min

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Introduction

Materials and Methods

Data Collection

Germline Genetic Analysis

Clinical Genetics SHORT REPORT OPEN ACCESS Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient Aasem Abu Shtaya1,2 | Yarin Hadid3 | Ahmad Mahamid4,5 | Debora Kidron6,7 | Naama Halpern7,8 | Adel Shalata3,5 | Zohar Levi7,9 | Yael Goldberg1,7 1Recanati Genetics Institute, Rabin Medical Center—Beilinson Hospital, Petach Tikva, Israel | 2Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa, Israel | 3Bnei Zion Medical Center, Simon Winter Institute for Human Genetics, Haifa, Israel | 4Department of Surgery, Carmel Medical Center, Haifa, Israel | 5The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel | 6Department of Pathology, Meir Hospital, Kfar Saba, Israel | 7Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel | 8The Jusidman Cancer Center, Sheba Medical Center, Ramat Gan, Israel | 9Division of Gastroenterology, Rabin Medical Center—Beilinson Hospital, Petach Tikva, Israel Correspondence: Yael Goldberg ([yaelgo43@gmail.com](yaelgo43@gmail.com)) Received: 19 April 2025 | Revised: 21 July 2025 | Accepted: 4 August 2025 Funding: The authors received no specific funding for this work. Keywords: cancer | colorectal | constitutional epimutation | lynch | methylation | MLH1 | MSH6 ABSTRACT Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. We report a 27-year-old woman with right-sided colorectal cancer, café-au-lait macules, and an occipital neurofibroma. Tumor testing revealed microsatellite instability, loss of MLH1 and PMS2 expression, high tumor mutational burden (21.87 mutations/Mb), and wild-type BRAF. Germline analysis revealed a heterozygous MSH6 pathogenic variant inherited from her father. Additionally, MLH1 promoter hypermethylation was detected in peripheral blood DNA, consistent with constitutional mosaic epimutation. Constitutional epigenetic silencing of MLH1 is a rare but established cause of LS. This is the first reported case of a dual mechanism involving both a germline MSH6 variant and constitutional MLH1 methylation. The patient's unique clinical presentation and molecular profile challenged the conventional binary classification of MMR deficiency as either hereditary or sporadic, and highlight the complexity of MMR-related tumorigenesis. This case underscores the importance ofcomprehensive assessment integrating tumor and germline molecular data, particularly when clinical or molecular findings are atypical or discordant. The digenic etiology also raises questions regarding cancer surveillance and management strategies in such individuals. 1 | Introduction Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants (PVs) in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 [1]. These genes play a role in maintaining genomic stability by correcting DNA replication errors. Approximately 1.5%– 4% of LS cases are caused by epigenetic events such as MSH2 silencing due to EPCAM deletions or MLH1 promoter hypermethylation [2–4] . Loss of MMR function leads to microsatellite instability (MSI), a hallmark of LS, which significantly increases the risk of colorectal, endometrial, and additional extracolonic malignancies [3] . Universal screening strategies, performed via immunohistochemistry (IHC) or MSI testing, have become a standard practice in identifying patients at risk for LS [5] . Loss of MLH1 and/or PMS2 expression is caused by either: (i) germline PVs, (ii) somatic MLH1 promoter hypermethylation, (iii) biallelic somatic MLH1 mutations, or rarely (iv) constitutional MLH1 hypermethylation [6] . In MMR-deficient colorectal This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided t

FAQs

What underlying genetic mechanism was found in the reported patient?

The patient had a heterozygous germline MSH6 pathogenic variant inherited from her father, together with constitutional MLH1 promoter hypermethylation consistent with constitutional mosaic epimutation.

What did tumor testing reveal about mismatch repair status?

Tumor testing showed microsatellite instability and loss of MLH1 and PMS2 expression, along with high tumor mutational burden and wild-type BRAF.

Why does this case challenge conventional Lynch syndrome classification?

The co-occurrence of a germline MSH6 variant and constitutional MLH1 methylation suggests a dual mechanism that complicates the usual binary distinction between hereditary and sporadic MMR deficiency, highlighting the need for integrated tumor and germline profiling.

Sep 30, 2026

Uploaded by Mabel