Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-only Comprehensive Genomic Profiling in a...

A 55-year-old woman was diagnosed with limited-disease small cell lung cancer (LD-SCLC) after incidental detection of a lung nodule. First-line chemotherapy achieved partial response, but recurrence occurred after one year. During second-line therapy, comprehensive genomic profiling (CGP) revealed a germline MSH6 frameshift mutation. Although lung tumor immunohistochemistry showed the retained expression of mismatch repair (MMR) protein, a prior colon cancer specimen showed the loss of MSH6 expression and deficient MMR expression. Germline genetic testing confirmed Lynch syndrome. Cascade testing identified the same mutation in her daughter. This case outlines a tumor-to-germline workflow with testing of at-risk relatives and highlights the importance of prudent interpretation of presumed germline variants.