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Methionine is a precursor for a major DNA methyl donor and is important for DNA methylation and gene regulation. Rare mutations in the <jats:italic>MTHFR<\/jats:italic> gene have been associated with autosomal recessive MTHFR deficiency leading to homocystinuria. In addition, two polymorphic variants in this gene (C677T and A1298C) have been implicated in a mild form of MTHFR deficiency associated with hyperhomocysteinemia. Mild to moderate hyperhomocysteinemia has been previously implicated as a risk factor for cardiovascular disease. Further, the presence of these variants, with and without mildly elevated levels of homocysteine, has been studied in relation to several multifactorial disorders including recurrent pregnancy loss, neural tube defects and congenital anomalies, cancer, and neurodevelopmental disorders. Given this wide spectrum of purported clinical implications and the prevalence of these polymorphisms, genetic counselors may encounter questions regarding the significance of <jats:italic>MTHFR<\/jats:italic> polymorphisms in a variety of settings. Here we present a brief background of the <jats:italic>MTHFR<\/jats:italic> polymorphisms, review of the literature regarding clinical considerations, and discussion of relevant genetic counseling aspects through case vignettes. Educational resources for patients and providers are also included.<\/jats:p>","DOI":"10.1007\/s10897-016-9956-7","type":"journal-article","created":{"date-parts":[[2016,4,30]],"date-time":"2016-04-30T01:24:28Z","timestamp":1461979468000},"page":"901-911","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence\u2010Based Literature"],"prefix":"10.1002","volume":"25","author":[{"given":"Brooke Levenseller","family":"Levin","sequence":"first","affiliation":[{"name":"MD Anderson Cancer Center at Cooper Cooper University Hospital 900 Centennial Boulevard, Suite M Voorhees NJ 08043 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Varga","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology\/BMT Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,4,30]]},"reference":[{"key":"e_1_2_13_2_1","unstructured":"Aetna Clinical Policy Bulletin(25 June2014).Homocysteine Testing. 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