Rare Intronic Variants Altering Splicing Cause Lynch Syndrome: Two Case Reports

Lynch syndrome (LS) is an autosomal-dominant hereditary cancer syndrome caused by defective mismatch repair (MMR) genes. This report presents two cases of LS with rare intronic variants in MLH1 and MSH2 that affect splicing, leading to diagnostic challenges and implications for management. The first case involves a 50-year-old woman with a history of colorectal and endometrial cancers, identified with a MSH2 c.2458+976A>G variant, resulting in pseudo-exon inclusion. The second case describes a 70-year-old woman with synchronous endometrial and cecal cancers, carrying an MLH1 c.545+4_545+5del variant, which caused exon 6 skipping. Both cases have strong familial and/or medical histories of LS-related cancers, but no pathogenic variant has been detected by conventional genetic testing. In these cases, RNA sequencing played a crucial role in establishing a definitive diagnosis. These findings highlight the need for genetic testing beyond conventional exon-focused sequencing to ensure accurate diagnosis and management.