BRCA1 is a tumor suppressor gene that was originally identified due to its linkage with breast cancer [Article:7545954], but is expressed in a variety of tissues [Article:16445371]. Many alternative splice forms have been identified, but only a few have been shown to be expressed. Alternative splicing may alter subcellular localization of the protein and possibly its ability to interact with other proteins [Articles:7545954, 16445371]. BRCA1 interacts with many different proteins to form multisubunit complexes that are involved in a host of cellular processes, however, the details of BRCA1 function have yet to be fully elucidated (reviewed in [Article:16445371]).
Mutations in BRCA1 have been shown to be associated with several types of cancer, most notably familial forms of breast cancer and ovarian cancer. One study showed 16 of 37 families at high risk for breast or breast and ovarian cancer have mutations in BRCA1 [Article:8533757]. Other studies of individuals with breast and/or ovarian cancer or at high risk for such cancers have shown that 9%-13% have deleterious mutations in BRCA1 [Articles:11896095, 9333265]. In addition, the presence of mutations in BRCA1 is associated with an increased risk for male breast cancer [Articles:11896095, 12237282]. Results are conflicting as to whether BRCA1 mutations confer an increased risk for prostate cancer [Articles:12237281, 12237282]. Mutation of BRCA1 is also associated with increased risk for pancreatic, uterine, cervical, colon, stomach, and fallopian tube cancers [Articles:12237281, 12237282]. For carriers of BRCA1 mutations, the risk of developing breast cancer by age 70 has been suggested to be between 56% and 90% [Articles:7825587, 12237282, 8460634, 9145676]. The risk of ovarian cancer by age 70 in BRCA1 mutation carriers has been suggested to be between 16% and 63% [Articles:9145676, 7825587, 12237282].
The Breast Cancer Mutation Database includes over 1700 different mutations that have been identified in BRCA1. Mutations in BRCA1 are generally classified as being deleterious (i.e. associated with cancer), neutral, or unclassified [Article:15254424]. Over 30% of the mutations in the Breast Cancer Mutation Database are missense mutations, many of which have been reported only once. These mutations prove difficult in risk assessment. The only potential regulatory mutations that have been identified are truncating mutations that cause nonsense-mediated RNA degradation [Article:15254424]. Altered promoter methylation has also been noted [Articles:11034065, 10208417]. Promoter methylation could silence gene expression and explain why loss of heterozygosity (LOH) in sporadic breast cancer is often not accompanied by mutation of the remaining allele [Article:10208417]. Mutations have also been found at every splice site in the gene. However, most mutations that have been documented are insertions, deletions, or nonsense mutations that lead to premature truncation of the protein [Article:15254424]. In one study, 86% of BRCA1 mutations found were predicted to produce a truncated protein [Article:7837387]. 185delAG and 5382insC are by far the most-widely studied mutations and are described as 'founder' mutations in the Ashkenazi Jew population (see variant pages for details). Clinical testing for BRCA1 mutations, either entire gene sequencing, or detection of founder mutations, is currently available.
Several haplotype analyses of BRCA1 mutations have been reported [Articles:12466288, 9333265, 15829246] PA150481229. These studies show that despite the large number of mutations identified thus far for BRCA1, most individuals can be segregated into a fairly small number of haplotypes. One analysis found four of ten haplotypes were present in all of the populations they studied (Asian-American, African-American, European-American, and Hispanic-American), and these four haplotypes together accounted for the majority of individuals in each population [Article:12466288]. By far the largest haplotype study on BRCA1 is by Judkins et al., from Myriad Genetic Laboratories PA150481229 [Article:15829246]. They analyzed data for 25,000 individuals and identified ten haplotypes based on 14 common biallelic polymorphisms. These ten haplotypes describe 99% of the chromosomes from the 25,000 individuals and fall into two distinct clades. See also [Articles:15829246, 12466288, 9333265] and BRCA1 Haplotypes: http://preview.pharmgkb.org/gene/PA25411#tabview=tab4&subtab=31.
Please Note: The BRCA1 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Submitted by Amy Hodge (July 17, 2006)
|Variant Summaries||chr17:41276046, chr17:41209080|