BRCA2

1 Function

BRCA2 and BRCA2 (/brktu/[1] ) are a human gene

and its protein product, respectively. The ocial symbol (BRCA2, italic for the gene, nonitalic for the protein)
and the ocial name (breast cancer 2, early onset) are
maintained by the HGNC. Orthologs, styled Brca2 and
Brca2, are common in other mammal species.[2] BRCA2
is a human tumor suppressor gene[3][4] (specically, 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.[5]

Although the structures of the BRCA1 and BRCA2 genes

are very dierent, 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 BRCA1PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2)[19] can function synergistically with a
BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[20] 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.

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.[6][7] 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.[8][9] 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.
Like BRCA1, BRCA2 probably regulates the activity of
The BRCA2 gene is located on the long (q) arm of other genes and plays a critical role in embryo developchromosome 13 at position 12.3 (13q12.3).[10] The hu- ment.
man reference BRCA 2 gene contains 27 exons, and the
cDNA has 10,254 base pairs[11] coding for a protein of
3418 amino acids.[12][13]

2 Clinical signicance

The gene was rst cloned by scientists at Myriad Genetics, Endo Recherche, Inc., HSC Research & DevelopFurther information: BRCA mutation
ment Limited Partnership, and the University of Penn[14]
sylvania.
Certain variations of the BRCA2 gene increase risks for
Methods to diagnose the likelihood of a patient with mubreast cancer as part of a hereditary breast-ovarian cantations in BRCA1 and BRCA2 getting cancer were covcer syndrome. Researchers have identied hundreds of
ered by patents owned or controlled by Myriad Genetmutations in the BRCA2 gene, many of which cause an
ics.[15][16] Myriads business model of exclusively oerincreased risk of cancer. BRCA2 mutations are usually
ing the diagnostic test led from Myriad being a startup in
insertions or deletions of a small number of DNA base
1994 to being a publicly traded company with 1200 empairs in the gene. As a result of these mutations, the proployees and about $500M in annual revenue in 2012;[17]
tein product of the BRCA2 gene is abnormal and does not
it also led to controversy over high prices and the infunction properly. Researchers believe that the defective
ability to get second opinions from other diagnostic labs,
BRCA2 protein is unable to help x mutations that occur
which in turn led to the landmark Association for Molecin other genes. As a result, mutations build up and can
[18]
ular Pathology v. Myriad Genetics lawsuit.
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 pro1

tein 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 specicity. Major
determinants of where BRCA1 and BRCA2 associated
hereditary cancers occur are related to tissue specicity
of the cancer pathogen, the agent that causes chronic inammation or the carcinogen. The target tissue may have
receptors for the pathogen, become selectively exposed
to carcinogens and an infectious process. An innate genomic decit impairs normal responses and exacerbates
the susceptibility to disease in organ targets. This theory also ts 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.[21]

INTERACTIONS

single BRCA2 (999del5) mutation accounts for virtually

all breast/ovarian cancer families.[26][27] 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 aect 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 an incomplete list that may never
be able to satisfy particular standards for
completeness. You can help by expanding it
with reliably sourced entries.

5 Interactions

In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian, BRCA2 has been shown to interact with
Fallopian tube, prostate, and pancreatic cancers, as well
as malignant melanoma. In some studies, mutations in
BRE,[43]
the central part of the gene have been associated with a
BARD1,[43][44]
higher risk of ovarian cancer and a lower risk of prostate
cancer than mutations in other parts of the gene. Sev BCCIP,[45]
eral other types of cancer have also been seen in certain
families with BRCA2 mutations.
BRCA1,[43][46][47][48]
In general, strongly inherited gene mutations (including
BRCC3,[43]
mutations in BRCA2) account for only 5-10% of breast
cancer cases; the specic risk of getting breast or other
BUB1B,[49]
cancer for anyone carrying a BRCA2 mutation depends
CREBBP,[50]
on many factors.[22]
C11orf30,[51]

History

Germ line BRCA2 mutations and

founder eect

FANCD2,[52][53][54]
FANCG,[55]
FLNA,[56]
HMG20B,[57][58]
P53,[43][59]

All germ line BRCA2 mutations identied to date have

been inherited, suggesting the possibility of a large
founder eect in which a certain mutation is common
to a well-dened 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.[25] A striking example of a founder mutation is found in Iceland, where a

PALB2,[19][60]
PCAF,[61][62]
PLK1,[61][63]
RAD51,[43][46][61][64][65][66][67][68][69][70][45][47][59]
RPA1,[71]
SHFM1[72][73] and
SMAD3.[74]

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.[59][66][67][75]

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
led by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994;[15] over the next year, Myriad, in collaboration with other investigators, isolated and sequenced
the BRCA2 gene and identied relevant mutations, and
the rst BRCA2 patent was led in the U.S. by Myriad
and the other institutions in 1995.[14] Myriad is the exclusive licensee of these patents and has enforced them
in the US against clinical diagnostic labs.[18] 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;[17] 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.[18][76] The patents begin to
expire in 2014.

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 identied as one of three genes that map to a 1.5-Mb
locus deleted in an inherited developmental malformation
According to an article published in the journal, Genetic
syndrome.[73]
Medicine, in 2010, The patent story outside the United
The BRCA OB1 domain assumes an OB fold, which con- States is more complicated.... For example, patents have
sists of a highly curved ve-stranded beta-sheet that closes been obtained but the patents are being ignored by provinon itself to form a beta-barrel. OB1 has a shallow groove cial health systems in Canada. In Australia and the
formed by one face of the curved sheet and is demar- UK, Myriads licensee permitted use by health systems,
cated by two loops, one between beta 1 and beta 2 and but announced a change of plans in August 2008. ...
another between beta 4 and beta 5, which allows for weak Only a single mutation has been patented in Myriads
single strand DNA binding. The domain also binds the lone European-wide patent, although some patents re70-amino acid DSS1 (deleted in split-hand/split foot syn- main under review of an opposition proceeding. In efdrome) protein.[73]
fect, the United States is the only jurisdiction where MyrThe BRCA OB3 domain assumes an OB fold, which con- iads strong patent position has conferred sole-provide
[77][78]
Peter Meldrum, CEO of Myriad Genetics,
sists of a highly curved ve-stranded beta-sheet that closes status.
on itself to form a beta-barrel. OB3 has a pronounced has acknowledged that Myriad has other competitive adgroove formed by one face of the curved sheet and is de- vantages that may make such [patent] enforcement un[79]
marcated by two loops, one between beta 1 and beta 2 necessary in Europe.
and another between beta 4 and beta 5, which allows for Legal decisions surrounding the BRCA1 and BRCA2
strong ssDNA binding.[73]
patents will aect the eld of genetic testing in
[80]
In June 2013, in Association for Molecular
The Tower domain adopts a secondary structure consist- general.
Pathology
v.
Myriad Genetics (No. 12-398), the US
ing of a pair of long, antiparallel alpha-helices (the stem)
Supreme
Court
unanimously ruled that, A naturally octhat support a three-helix bundle (3HB) at their end. The
curring
DNA
segment
is a product of nature and not
3HB contains a helix-turn-helix motif and is similar to
patent
eligible
merely
because
it has been isolated, inthe DNA binding domains of the bacterial site-specic
validating
Myriads
patents
on
the
BRCA1 and BRCA2
recombinases, and of eukaryotic Myb and homeodomain
genes.
However,
the
Court
also
held
that manipulation of
transcription factors. The Tower domain has an impora
gene
to
create
something
not
found
in nature could still
tant role in the tumour suppressor function of BRCA2,
[81]
The
Federal Court of
be
eligible
for
patent
protection.
and is essential for appropriate binding of BRCA2 to
[73]
Australia
came
to
the
opposite
conclusion,
upholding the
DNA.
validity of an Australian Myriad Genetics patent over the
BRCA1 gene in February 2013,[82] but this decision is
being appealed and the appeal will include consideration
7 Patents, enforcement, litigation, of the US Supreme Court ruling.[83]

and controversy
Main article: Association for Molecular Pathology v.
Myriad Genetics

8 See also
BRCA1

9
DNA repair
PALB2

References

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11

11

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
FORCE: Facing Our Risk of Cancer Empowered - Hereditary, Genetic Breast or Ovarian Cancer and
BRCA Issues. Facing Our Risk of Cancer Empowered, Inc. Archived from the original on 29 September 2008. Retrieved 2008-10-11.
UCSC Genome Browser View
den Dunnen JT, Antonarakis SE (2000). Mutation
nomenclature extensions and suggestions to describe complex mutations: A discussion. Human
Mutation 15 (1): 712. doi:10.1002/(SICI)10981004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N.
PMID 10612815.
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

EXTERNAL LINKS

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