A novel gene was identified recently at chromosome 10q23, named PTEN or MMAC1, and based on several criteria it was designated as a potential human tumor suppressor gene. Loss of heterozygosity affecting this region of 10q is observed in several cancer types, especially glioblastoma, and inactivating mutations of the PTEN/MMAC1 gene are found in some of these cancers as well as cell lines and xenografts. Breast cancer is among the tumor types in which mutations are documented, and germline mutations of the gene appear to be responsible for the rare autosomal dominant familial cancer syndrome known as Cowden disease, which includes breast cancer among its clinical features. To further determine the role that PTEN/MMAC1 mutations may play in breast tumorigenesis, the entire coding region was screened for mutations in 54 unselected primary breast cancers. Two mutations were identified, a somatic 2-bp deletion in an apparently sporadic breast cancer, and a germ-line 4-bp deletion in a breast cancer patient with a clinical history consistent with Cowden disease. These data indicate that somatic mutations of PTEN/ MMAC1 occur in only a small fraction of primary breast cancers and confirm the role of this gene in the etiology of Cowden disease. Evidence is also presented suggesting that numerous polymorphisms and missense variants exist in the PTEN/MMAC1 transcript.