Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome

Abstract

Whole-genome sequencing can uncover clinically significant noncoding variants missed by standard germline testing, as demonstrated in this report in a patient with Muir-Torre syndrome, a subtype of Lynch syndrome. In this case, despite a convincing clinical phenotype and immunohistochemical loss of MSH2/MSH6 in 1 of the patient's tumors, conventional gene panel testing failed to detect a germline pathogenic variant. Wholegenome sequencing identified a deep intronic MSH2 variant, and tumor sequencing revealed somatic MSH2 mutations (second hits) across multiple tumors, confirming mismatch repair deficiency and establishing a MuirTorre syndrome diagnosis. This report underscores the limitations of routine genetic testing and highlights the clinical utility of whole-genome sequencing in identifying pathogenic variants in noncoding regions. It also emphasizes the role of dermatologists in recognizing cutaneous markers of hereditary cancer syndromes and the importance of interdisciplinary evaluation in guiding both patient care and familial risk assessment.