BRCA2

Template:PBB BRCA2 (Breast Cancer 2 susceptibility protein) is a protein that in humans is encoded by the BRCA2 gene. BRCA2 orthologs have been identified in most mammals for which complete genome data are available. BRCA2 belongs to the tumor suppressor gene family and the protein encoded by this gene is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3), from base pair 31,787,616 to base pair 31,871,804.

Function

Although the structures of the BRCA1 and BRCA2 genes are very different, at least some functions are interrelated. The proteins made by both genes are essential for repairing damaged DNA. The BRCA2 protein binds to and regulates the protein produced by the RAD51 gene to fix breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, but also occur when chromosomes exchange genetic material during a special type of cell division that creates sperm and eggs (meiosis). The BRCA1 protein also interacts with the RAD51 protein. By repairing DNA, these three proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic cancers.

Like BRCA1, BRCA2 probably regulates the activity of other genes and plays a critical role in embryo development.

Clinical significance

Further information: BRCA mutation

Certain variations of the BRCA2 gene cause an increased risk for breast cancer. Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs (the building material of chromosomes) in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal and does not function properly. Researchers believe that the defective BRCA2 protein is unable to help fix mutations that occur in other genes. As a result, mutations build up and can cause cells to divide in an uncontrolled way and form a tumor.

People who have two mutated copies of the BRCA2 gene have one type of Fanconi anemia. This condition is caused by extremely reduced levels of the BRCA2 protein in cells, which allows the accumulation of damaged DNA. Patients with Fanconi anemia are prone to several types of leukemia (a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and reproductive organs; and bone marrow suppression (reduced blood cell production that leads to anemia). A pathogenic mutation almost anywhere in a model pathway for DNA double strand break repair containing BRCA1 and BRCA2 greatly increases the risks for a subgroup of lymphomas and leukemia.

In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian, Fallopian tube, prostate, and pancreatic cancers, as well as malignant melanoma. In some studies, mutations in the central part of the gene have been associated with a higher risk of ovarian cancer and a lower risk of prostate cancer than mutations in other parts of the gene. Several other types of cancer have also been seen in certain families with BRCA2 mutations.

History

The BRCA2 gene was discovered in 1994 by Professor Michael Stratton and Dr Richard Wooster (Institute of Cancer Research, UK). The Wellcome Trust Sanger Institute (Hinxton, Cambs, UK) collaborated with Stratton and Wooster to isolate the gene. In honour of this discovery and collaboration, the Wellcome Trust has participated in the construction of a cycle path between Addenbrooke's Hospital site in Cambridge and the nearby village of Great Shelford. It is decorated with over 10,000 lines of 4 colours representing the nucleotide sequence of BRCA2. It makes up part of the National Cycle Network route 11, and can be seen from the Cambridge-London Liverpool Street train.

Germ line BRCA2 mutations and founder effect

All germ line BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large “founder” effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor. Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations. Analysis of mutations that occur with high frequency also permits the study of their clinical expression. A striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families. This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease. This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.

This is a dynamic list and may never be able to satisfy particular standards for completeness. You can help by adding missing items with reliable sources.

Population or subgroup	BRCA2 mutation(s)	Reference(s)
Ashkenazi Jewish	6174delT
Dutch	5579insA
Finns	8555T>G, 999del5, IVS23-2A>G
French Canadians	8765delAG
Germans
Hungarians	9326insA
Icelandics	999del5
Italians	8765delAG
Northern Irish	6503delTT
Pakistanis	3337C>T
Scottish	6503delTT
Slovenians	IVS16-2A>G
Spanish	3034delAAAC(codon936), 9254del5
Swedish	4486delG

Interactions

BRCA2 has been shown to interact with

• BRE,
• BARD1,
• BCCIP,
• BRCA1,
• BRCC3,
• BUB1B,
• C11orf30,
• FANCD2,
• FANCG,
• FLNA,
• HMG20B,
• P53,
• PCAF,
• PLK1,
• RAD51,
• RPA1,
• SHFM1 and
• SMAD3.

See also

• BRCA1
• DNA repair
• Cancer

External links

• BRCA2 Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
• EntrezGene 675
• GeneCard
• Cancer.gov
• "FORCE: Facing Our Risk of Cancer Empowered -- Hereditary, Genetic Breast or Ovarian Cancer and BRCA Issues". Facing Our Risk of Cancer Empowered, Inc. Retrieved 2008-10-11. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
• UCSC Genome Browser View
• Johan T. den Dunnen. "A mutation nomenclature for BRCA2 mutations". Wiley Interscience. Retrieved 2010-02-10. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
• UCSC Gene details page