Hereditary Non-Polyposis Colon Cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant syndrome that predisposes to malignancy, including lifetime risk of up to 80% for early onset of colorectal cancer. Individuals affected with HNPCC are also at increased risk for developing tumors in the ovaries, endometrium, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain and skin. Muir-Torre syndrome and Turcot syndrome are clinical variants of HNPCC. Moreover, they can involve germ-line mutations in the same genes.

The diagnosis of Lynch syndrome can be made on the basis of family history in those families meeting the Amsterdam criteria who have tumor microsatellite instability (MSI) or on the basis of molecular genetic testing in an individual or family with a germline mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). MLH1 and MSH2 germline mutations account for approximately 90% of mutations in families with Lynch syndrome; MSH6 mutations in about 7%-10%; and PMS2 mutations in fewer than 5%. Germline deletions in EPCAM (not a mismatch repair gene) inactivate MSH2 in about 1% of individuals with Lynch syndrome.

Genetic testing for Lynch syndrome is ideally performed in a stepwise manner:

1. Evaluation of tumor tissue for MSI through MSI testing by PCR and/or immunohistochemistry (IHC) of the four MMR proteins. The presence of MSI in the tumor by itself is not sufficient to diagnosis Lynch syndrome because 10%-15% of sporadic colorectal cancers exhibit MSI. IHC can help identify the MMR gene that most likely harbors a germline mutation and guide molecular genetic testing.

2. Molecular genetic testing of the tumor for MLH1 hypermethylation and somatic BRAF mutations to help identify those tumors more likely to be sporadic than hereditary.

3. Molecular genetic testing of DNA from peripheral blood/normal tissue of the MMR genes to identify a germline mutation when findings are consistent with Lynch syndrome.