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

TL;DR

A young woman with colorectal cancer had both a genetic mutation and an epigenetic change linked to Lynch syndrome, showing a complex cause of the disease.

Contribution

This is the first reported case combining a germline MSH6 variant with constitutional MLH1 methylation in a Lynch syndrome patient.

Findings

The patient had a germline MSH6 pathogenic variant inherited from her father.

Constitutional MLH1 promoter hypermethylation was detected in peripheral blood DNA.

The case represents a dual mechanism of MMR deficiency involving both genetic and epigenetic factors.

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 of comprehensive 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.

We report a unique case of early‐onset colorectal cancer with both a germline MSH6 variant and constitutional mosaic MLH1 epimutation, revealing a possible digenic mechanism underlying Lynch syndrome. This case highlights the diagnostic complexity of mismatch repair deficiency and the value of integrative tumor–germline molecular profiling.

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