# Uncovering a Novel Homozygous MSH6 Variant in a Child Presenting With Glioblastoma: A Case of Constitutional Mismatch Repair Deficiency

## TL;DR

A child with glioblastoma and T-lymphoblastic lymphoma was found to have a rare genetic disorder due to a previously unreported MSH6 mutation.

## Contribution

This case reports a novel homozygous MSH6 variant confirmed to be pathogenic in a child with CMMRD.

## Key findings

- A homozygous MSH6 variant (c.3680T>G, p.Ile1227Arg) was identified in a child with CMMRD.
- The variant was classified as likely pathogenic based on ACMG criteria and clinical evidence.
- The case highlights the importance of multidisciplinary evaluation for accurate CMMRD diagnosis.

## Abstract

Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. We report a previously healthy seven-year-old boy who presented with a high-grade glioma and was later diagnosed with T-lymphoblastic lymphoma (TLL). Immunohistochemistry (IHC) of the brain tumor showed partial loss of MSH6 expression in both tumor and adjacent normal cells. Genetic testing identified a homozygous MSH6 variant (c.3680T>G, p.Ile1227Arg), with both parents confirmed as heterozygous carriers. This variant has not previously been reported in the homozygous state with clear clinical correlation. The combined clinical, histologic, and genetic findings strongly support a diagnosis of CMMRD and fulfill multiple American College of Medical Genetics and Genomics (ACMG) criteria, supporting reclassification of this variant as likely pathogenic. This case is notable for providing one of the few documented homozygous MSH6 mutations with a well-defined childhood CMMRD phenotype. It underscores the importance of integrating clinical, radiologic, histologic, and genetic evidence for accurate diagnosis, guiding surveillance, treatment, and family counseling.