Muir–Torre Syndrome Associated With a Cryptic Intronic MSH2 Variant Identified via Whole‐Genome Sequencing: A Case Report

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Tumors exhibiting mismatch repair deficiency without detectable germline mutations via standard multigene panel testing are often classified as Lynch-like syndrome. In the present report, we describe the case of a 47-year-old man presenting with synchronous axillary sebaceous carcinoma and colonic medullary carcinoma. Although initial germline multigene panel testing failed to identify pathogenic variants, a high degree of pathological suspicion for Muir-Torre syndrome remained. Immunohistochemistry revealed a concordant loss of MSH2 and MSH6 expression in both the extraocular sebaceous carcinoma and the colonic medullary carcinoma. This identical protein-loss pattern detected across anatomically distinct tumors served as decisive pathological evidence of an underlying germline defect rather than independent biallelic somatic mutations. Consequently, whole-genome sequencing was performed to resolve the discrepancy between the pathological findings and multigene panel testing results, successfully identifying a germline intronic MSH2 variant (NM_000251.3:c.2459-12A>G). Subsequent RNA analysis confirmed aberrant splicing with an 11-bp insertion. In conclusion, the present case illustrates that concordant mismatch repair protein loss across multiple tumors provides compelling morphological evidence to guide pathologists in reconsidering negative panel results and pursuing comprehensive genomic investigation to identify pathogenic intronic variants.

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