Identification and pathogenicity validation of a novel MLH1 frameshift mutation in Lynch syndrome pedigree

Lynch syndrome (LS), the most prevalent hereditary colorectal cancer (CRC) syndrome, accounts for approximately 2 %-3 % of all CRC cases and confers a significantly elevated cancer risk among affected family members, necessitating targeted preventive interventions. This study examined a 40-year-old female proband diagnosed with colon cancer at the First Affiliated Hospital of Kunming Medical University in October 2020, who fulfilled the Amsterdam II criteria. The four-generation pedigree comprised 42 members, including 9 individuals with malignant tumors and an average age of onset of 44.3 years, consistent with classical LS family features. Following the collection of blood samples, clinical data, and pedigree construction, next-generation sequencing (NGS) of the proband revealed a novel germline frameshift mutation in MLH1 exon 6: c.463dupC (p.L155Pfs*17). Subsequent Sanger sequencing of 20 first-degree relatives confirmed the variant in 7 carriers, including 3 individuals with confirmed colon cancer, demonstrating complete co-segregation of the mutation with the disease phenotype.