Follow-up evaluation in individuals with hyperhomocysteinemia. Hyperhomocysteinemia is multifactorial, involving genetic, clinical, and environmental risk factors. Reduced enzyme activity of methylenetetrahydrofolate reductase (MTHFR) is a genetic risk factor for hyperhomocysteinemia, particularly when serum folate levels are low. There are two common variants in the MTHFR gene that can decrease enzyme activity: c.665C>T (p. Ala222Val), legacy name C677T, and c.1286A>C (p. Glu429Ala), legacy name A1298C. These variants do not independently increase risk of conditions related to hyperhomocysteinemia in the absence of elevated homocysteine levels. Measurement of total plasma homocysteine is recommended. Patients should share their MTHFR genotype with physicians who are making decisions regarding chemotherapy treatments that depend on folate, such as methotrexate. Guidelines do not recommend genotyping of these two MTHFR variants in the evaluation of venous thromboembolism or obstetric risk due to limited evidence of clinical utility. Genetic coordinators are available for health care providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.