The 3-2-1 rule refers to the Amsterdam II criteria for identifying families with a high risk of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. The rule is a mnemonic for the three criteria that must all be met: three or more relatives with Lynch syndrome-related cancers (like colorectal or endometrial), two successive generations with affected family members, and at least one relative diagnosed before age 50.