BRCA2

Breast cancer 2, early onset
PDB rendering based on 1n0w.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1N0W, 3EU7
Identifiers
Symbols	BRCA2 ; BRCC2; BROVCA2; FACD; FAD; FAD1; FANCD; FANCD1; GLM3; PNCA2; XRCC11
External IDs	OMIM: 600185 MGI: 109337 HomoloGene: 41 GeneCards: BRCA2 Gene
Gene ontology Molecular function • protease binding • single-stranded DNA binding • histone acetyltransferase activity • protein binding • H3 histone acetyltransferase activity • H4 histone acetyltransferase activity • gamma-tubulin binding Cellular component • nucleus • nucleoplasm • cytoplasm • centrosome • secretory granule • BRCA2-MAGE-D1 complex • protein complex Biological process • double-strand break repair via homologous recombination • cytokinesis • oocyte maturation • inner cell mass cell proliferation • DNA repair • nucleotide-excision repair • double-strand break repair • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • male meiosis I • spermatogenesis • brain development • cell aging • response to nutrient • female gonad development • response to X-ray • response to UV-C • response to gamma radiation • hemopoiesis • mammary gland development • homologous chromosome orientation involved in meiotic metaphase I plate congression • response to estradiol • regulation of cytokinesis • negative regulation of mammary gland epithelial cell proliferation • multicellular organism growth • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • histone H3 acetylation • histone H4 acetylation • positive regulation of transcription, DNA-templated • positive regulation of mitotic cell cycle • replication fork protection • chromosome organization • centrosome duplication Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	675	12190
Ensembl	ENSG00000139618	ENSMUSG00000041147
UniProt	P51587	P97929
RefSeq (mRNA)	NM_000059	NM_001081001
RefSeq (protein)	NP_000050	NP_001074470
Location (UCSC)	Chr 13: 32.32 – 32.4 Mb	Chr 5: 150.52 – 150.57 Mb
PubMed search	[1]	[2]

BRCA2 repeat
crystal structure of a rad51-brca2 brc repeat complex
Identifiers
Symbol	BRCA2
Pfam	PF00634
InterPro	IPR002093
SCOP	1n0w
SUPERFAMILY	1n0w
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

BRCA-2 helical
structure of a brca2-dss1 complex
Identifiers
Symbol	BRCA-2_helical
Pfam	PF09169
InterPro	IPR015252
SCOP	1iyj
SUPERFAMILY	1iyj
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

BRCA2, oligonucleotide/oligosaccharide-binding, domain 1
structure of a brca2-dss1 complex
Identifiers
Symbol	BRCA-2_OB1
Pfam	PF09103
InterPro	IPR015187
SCOP	1iyj
SUPERFAMILY	1iyj
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

BRCA2, oligonucleotide/oligosaccharide-binding, domain 3
structure of a brca2-dss1 complex
Identifiers
Symbol	BRCA-2_OB3
Pfam	PF09104
InterPro	IPR015188
SCOP	1iyj
SUPERFAMILY	1iyj
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Tower domain
structure of a brca2-dss1 complex
Identifiers
Symbol	Tower
Pfam	PF09121
InterPro	IPR015205
SCOP	1mje
SUPERFAMILY	1mje
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

BRCA2 and BRCA2 (/ˌbrækəˈtuː/) are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (breast cancer 2) are maintained by the HGNC. Orthologs, styled Brca2 and Brca2, are common in other mammal species. BRCA2 is a human tumor suppressor gene (specifically, a caretaker gene), found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks. If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer. Thus, although the terms "breast cancer susceptibility gene" and "breast cancer susceptibility protein" (used frequently both in and outside the medical literature) sound as if they describe a proto-oncogene or oncogene, BRCA1 and BRCA2 are "normal"; it is their mutation that is abnormal.

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3). The human reference BRCA 2 gene contains 28 exons, and the cDNA has 10,254 base pairs coding for a protein of 3418 amino acids.

The gene was first cloned by scientists at Myriad Genetics, Endo Recherche, Inc., HSC Research & Development Limited Partnership, and the University of Pennsylvania.

Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting cancer were covered by patents owned or controlled by Myriad Genetics. Myriad's business model of exclusively offering the diagnostic test led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.

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. BRCA2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion a vital step of homologous recombination. The localization of RAD51 to the DNA double-strand break requires the formation of BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2) can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. 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). Double strand breaks are also generated during repair of DNA cross links. By repairing DNA, these proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic and other 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 increase risks for breast cancer as part of a hereditary breast-ovarian cancer syndrome. 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 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). Women having inherited a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1 and BRCA2 associated hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, become selectively exposed to carcinogens and an infectious process. An innate genomic deficit impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there are some options in addition to prophylactic surgery.

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.

In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.

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 participated in the construction of a cycle and foot path between the Addenbrooke's Hospital site in Cambridge and the nearby village of Great Shelford in 2005. The path by Cambridgeshire County Council and Sustrans is decorated with 10,257 stripes of 4 colours representing the nucleotide sequence of BRCA2 (green representing adenine, blue representing cytosine, yellow representing guanine, and red representing thymine). It makes up part of National Cycle Route 11, and can be seen from trains running between Cambridge and London.

File:DNA cyclepath to Shelford - geograph.org.uk - 538440.jpg The start of the cycle path

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 expanding it with reliably sourced entries.

Population or subgroup	BRCA2 mutation(s)	Reference(s)
Ashkenazi Jewish	6174delT
Dutch	5579insA
Finns	8555T>G, 999del5, IVS23-2A>G
French Canadians	8765delAG, 3398delAAAAG
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,
• CREBBP,
• C11orf30,
• FANCD2,
• FANCG,
• FLNA,
• HMG20B,
• P53,
• PALB2,
• PCAF,
• PLK1,
• RAD51,
• RPA1,
• SHFM1 and
• SMAD3.

Domain architecture

BRCA2 contains a number of 39 amino acid repeats that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment.

The BRCA2 helical domain adopts a helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive beta-hairpins (beta 1 to beta 4). An approximately 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure. In BRCA2, the alpha 9 and alpha 10 helices pack with the BRCA2 OB1 domain through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. This domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome.

The BRCA OB1 domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB1 has a shallow groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for weak single strand DNA binding. The domain also binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein.

The BRCA OB3 domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB3 has a pronounced groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for strong ssDNA binding.

The Tower domain adopts a secondary structure consisting of a pair of long, antiparallel alpha-helices (the stem) that support a three-helix bundle (3HB) at their end. The 3HB contains a helix-turn-helix motif and is similar to the DNA binding domains of the bacterial site-specific recombinases, and of eukaryotic Myb and homeodomain transcription factors. The Tower domain has an important role in the tumour suppressor function of BRCA2, and is essential for appropriate binding of BRCA2 to DNA.

Patents, enforcement, litigation, and controversy

Main article: Association for Molecular Pathology v. Myriad Genetics

A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994; over the next year, Myriad, in collaboration with other investigators, isolated and sequenced the BRCA2 gene and identified relevant mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and the other institutions in 1995. Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs. This business model led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit. The patents begin to expire in 2014.

According to an article published in the journal, Genetic Medicine, in 2010, "The patent story outside the United States is more complicated.... For example, patents have been obtained but the patents are being ignored by provincial health systems in Canada. In Australia and the UK, Myriad’s licensee permitted use by health systems, but announced a change of plans in August 2008. ... Only a single mutation has been patented in Myriad’s lone European-wide patent, although some patents remain under review of an opposition proceeding. In effect, the United States is the only jurisdiction where Myriad’s strong patent position has conferred sole-provide status." Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.

Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of genetic testing in general. In June 2013, in Association for Molecular Pathology v. Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection. The Federal Court of Australia came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013, but this decision is being appealed and the appeal will include consideration of the US Supreme Court ruling.

See also

• BRCA1
• DNA repair
• PALB2

External links

• BRCA2 Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
• OMIM entries on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
• EntrezGene 675
• GeneCard
• Cancer.gov
• UCSC Genome Browser View
• UCSC Gene details page

This article incorporates text from the public domain Pfam and InterPro IPR002093

This article incorporates text from the public domain Pfam and InterPro IPR015252

This article incorporates text from the public domain Pfam and InterPro IPR015187

This article incorporates text from the public domain Pfam and InterPro IPR015205