title: Identification of missense and truncating mutations in the BRCA1 gene in sporadic and familial breast and ovarian cancer.
abstract: The cloning of the breast and ovarian cancer susceptibility gene, BRCA1, allows direct estimation of the proportion of these cancers in the general population which can be attributed to germline mutations in this gene. We have used a combination of SSCP, heteroduplex analysis, and chemical cleavage of mismatch to screen the BRCA1 gene for mutations in the germline of 42 patients with breast or ovarian cancer who either have a moderate family history of these cancers, or have no family history of malignancy but a very early onset of the disease. A total of 30 sequence variants were observed, eight of which have not been described previously. Three sequence changes detected by chemical cleavage or heteroduplex analysis were missed by SSCP. The variants included 13 missense mutations, which were assessed for their pathogenic implications. Two of these (M18T and A1708E) are nonconservative substitutions which are located in evolutionarily conserved regions of the gene: M18T lies just upstream of the RING finger motif, and A1708E abolishes the transcriptional transactivation activity of the carboxy-terminal region of BRCA1. Mutations were observed in eight patients overall (19.0%), and protein-truncating mutations occurred in five of 27 (18.5%) families with 1-3 cases of breast or ovarian cancer. The data suggest that a significant proportion of patients with a modest or no family history of these cancers may carry germline mutations in BRCA1.
authors.affiliation: Division of Medical and Molecular Genetics, United Medical School, Guy's Hospital, London, England.
authors.forename: J
authors.initials: J
authors.lastname: Greenman
authors.forename: S
authors.initials: S
authors.lastname: Mohammed
authors.forename: D
authors.initials: D
authors.lastname: Ellis
authors.forename: S
authors.initials: S
authors.lastname: Watts
authors.forename: G
authors.initials: G
authors.lastname: Scott
authors.forename: L
authors.initials: L
authors.lastname: Izatt
authors.forename: D
authors.initials: D
authors.lastname: Barnes
authors.forename: E
authors.initials: E
authors.lastname: Solomon
authors.forename: S
authors.initials: S
authors.lastname: Hodgson
authors.forename: C
authors.initials: C
authors.lastname: Mathew
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein