Insertion of an Alu‐like element in MLH1 intron 7 as a novel cause of Lynch syndrome

BACKGROUND: Lynch Syndrome (LS) is caused by germline mutations in the DNA mismatch repair (MMR) genes with mutations in MLH1 accounting for ~40% of LS‐related alterations. METHODS: MSK‐IMPACT analysis was performed on peripheral blood from a patient with early‐ onset colorectal cancer. Subsequently PCR and sequencing was performed to characterize the insertion. Immunohistochemistry for MMR genes and MLH1 promoter methylation were analyzed on patient's tumor. RESULTS: MSK‐IMPACT germline testing revealed an insertion into c.588+8_588+9 of MLH1 intron 7. The insertion was further characterized as an AluSx‐like element with ~115 bp in length. Functional studies demonstrated that the AluSx‐like element led to complete disruption of mRNA splicing and probably resulted in transcriptional termination at the poly (A) region of the AluSx‐like insertion. CONCLUSIONS: The insertion of a truncated AluSx like element into MLH1 intron 7 results in aberrant splicing and transcription, thereby causing Lynch syndrome. This study confirms that retrotransposon insertions may be an important mechanism for cancer predisposition.