A novel deletion in the splice donor site of MLH1 exon 6 in a Japanese colon cancer patient with Lynch syndrome

Lynch syndromeis an autosomal dominantly inherited disease that is characterized bya predisposition tocancers,mainlycolorectalcancer.GermlinemutationsofDNAmismatchrepairgenessuchasMLH1, MSH2, MSH6 and PMS2 have been described in patients with Lynch syndrome. Here, we report deletion of 2 bp in the splice donor site of the MLH1 exon 6 (c.545+4_545+5delCA) in a 48-year-old Japanesewoman with Lynch syndrome. RT-PCRdirect sequencing analysis revealedthat this mutation led to an increase in the level of anMLH1 transcript in which exon 6 was skipped, and may cause a frameshift (p.E153FfsX8). Therefore, this mutation appears to be pathogenic and is responsible for Lynch syndrome. Additionally, analysis of the patient's tumor cells indicated microsatellite instability high phenotype and loss of the MLH1 and PMS2 proteins. To our knowledge, this is a germline splice site mutation of MLH1 that has not been reported previously.