Phenotypic heterogeneity in carriers of a pathogenic MSH2 variant - implications for the diagnosis of Lynch syndrome

Sep 22, 2026

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Lynch syndrome is an inherited cancer predisposition caused by germline pathogenic mismatch repair (MMR) gene variants and is classically linked to microsatellite instability (MSI) and loss of MMR protein expression by immunohistochemistry (IHC). Four cases from three unrelated families with the same pathogenic MSH2 variant were studied to define molecular and pathological features. MSI and MMR protein expression were assessed in available tumors, revealing heterogeneous MSI/IHC patterns across carriers. The findings indicate that identical MSH2 variants can yield variable tumor-level MMR/MSI phenotypes.

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Journal of Cancer Research and Clinical Oncology (2026) 152:162 [https://doi.org/10.1007/s00432-026-06526-5](https://doi.org/10.1007/s00432-026-06526-5) CASE REPORT Phenotypic heterogeneity in carriers of a pathogenic MSH2 variant: implications for the diagnosis of Lynch syndrome Tuna Apuhan1 · Oguzhan Demir1 · Zeynep SagnakYilmaz3 · Elanur Karaman4 · Ayberk Turkyilmaz1,2 · Alper Han Cebi1 Received: 13 April 2026 / Accepted: 27 May 2026 © The Author(s) 2026 Abstract Background: Lynch syndrome is an inherited cancer predisposition syndrome caused by germline pathogenic variants in mismatch repair (MMR) genes and is primarily associated with colorectal and endometrial cancers. Classically, Lynch syndrome-associated tumors exhibit microsatellite instability (MSI) and loss of MMR protein expression on immunohistochemistry (IHC); therefore, MSI and IHC are routinely used in screening algorithms to support diagnostic evaluation.; Methods: In this study, we present the molecular and pathological characteristics of four cases from three unrelated families carrying the same MSH2 variant [c.70C >T (p.Gln24Ter)], interpreted as pathogenic, who were diagnosed with breast and colorectal cancer. MSI analysis and MMR protein expression were evaluated in available tumor tissues. ; Results: Preserved MMR protein expression was observed in three cases, and two cases were microsatellite stable (MSS), whereas only one case demonstrated loss of MMR protein expression and an MSI-high phenotype consistent with the classical Lynch syndrome profile. These findings suggest that individuals carrying the same MSH2 variant may exhibit heterogeneous tumor-level MMR/MSI phenotypes. Early truncating variants in MSH2 may allow partially functional protein production via alternative translation initiation, potentially limiting complete loss of MMR function. Variability in somatic second-hit mechanisms and tumor-specific molecular pathways may also contribute to this heterogeneity. ; Conclusion: In conclusion, Lynch syndrome tumor biology may be more heterogeneous than expected, and MSI and IHC should not be interpreted in isolation as exclusionary tests for an underlying germline MMR variant, but rather as markers of tumorlevel biological consequences. Therefore, germline findings, tumor characteristics, and family history should be evaluated together in Lynch syndrome diagnosis and risk assessment. Keywords Lynch syndrome · MSH2 · Alternative translation initiation · Mismatch repair · Phenotypic heterogeneity 􀀍 Alper Han Cebi[dralphancebi@ktu.edu.tr](dralphancebi@ktu.edu.tr) 1 Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey 2 Present address: Gelisim Medical Laboratory, Istanbul, Turkey 3 Department of Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey 4 Department of Medical Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey Introduction Mismatch repair (MMR) genes take role in many basic cellular processes such as fixing the errors that occur during DNA synthesis, repair of double stranded DNA breaks, control of the anti-recombination processes and maintenance of DNA stability. Germline heterozygous pathogenic variants in the MMR genes MSH2, MLH1, MSH6 or PMS2, which are involved in this pathway, lead to Lynch Syndrome (Peltomäki 2003; Lynch et al. 2009) . Lynch syndrome is characterized by an increased risk of various cancers, primarily colon and endometrial cancer, but also ovarian, stomach, urinary system, brain, skin, and other cancers (Lynch et al. 2015; Mao et al. 2021) . Lynch syndrome is generally recognized as a condition characterized by the co-occurrence of associated cancers with microsatellite instability-high (MSI-H) . For individuals with colorectal cancer or endometrial cancer, MSI testing and/or IHC for MMR proteins is universally recommended for Lynch syndrome screening; additional testing criteria

FAQs

What is the focus of this case report?

The report examines phenotypic heterogeneity among carriers of a pathogenic MSH2 variant and how this affects diagnostic evaluation for Lynch syndrome.

Which MMR and MSI tests were used in the study?

The study evaluated microsatellite instability (MSI) and MMR protein expression by immunohistochemistry in available tumor tissues.

What did the results show about MSH2 carriers with the same variant?

Although three cases showed preserved MMR protein expression, two were microsatellite stable, and only one demonstrated loss of MMR protein expression with an MSI-high phenotype consistent with the classical profile.

Sep 22, 2026

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