Microsatellite stable colorectal cancers in clinically suspected hereditary nonpolyposis colorectal cancer patients without vertical transmission of disease are unlikely to be caused by biallelic germline mutations in MYH.

Microsatellite analysis and immunohistochemistry are commonly used initial screening tests for hereditary nonpolyposis colorectal cancer. However, tumors in roughly one-half of the patients fulfilling the Bethesda guidelines are microsatellite stable. In addition, normal mismatch repair protein expression in these tumors suggests that a defect in the mismatch repair system is unlikely. Because biallelic MYH mutations occur in patients with both high and low numbers of adenomas, we hypothesized that MYH is involved in the tumorigenesis of microsatellite stable colorectal cancers in patients without vertical transmission of disease and who fulfill the Bethesda guidelines. MYH was analyzed in 50 cancer patients and 116 healthy controls by complete genomic DNA sequencing. No biallelic germline mutations were identified. One patient was a heterozygous carrier for the p.G382D missense mutation, and another patient was a heterozygous carrier for the novel missense mutation p.Q484H. We identified six common variants, three in the coding region (p.V22M, p.Q324H, and p.S501F) and three in adjacent intronic regions (c.157+30A>G, c.462+35G>A, and c.1435-40G>C). In summary, biallelic germline mutations of MYH are unlikely to cause colorectal cancer in patients sharing clinical features with hereditary nonpolyposis colorectal cancer families without mismatch repair defect and therefore cannot fill the molecular diagnostic gap in this subgroup of Bethesda-positive patients.