View source for BRCA2

{{short description|Gene known for its role in breast cancer}}
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{{Infobox_gene}}
'''''BRCA2''''' and '''BRCA2''' ({{IPAc-en|ˌ|b|r|æ|k|ə|ˈ|t|uː}}<ref>{{cite web | url = http://www.healthcentral.com/breast-cancer/c/78/9925/brca1-brca2 | author = Hamel PJ | title = BRCA1 and BRCA2: No Longer the Only Troublesome Genes Out There | publisher = HealthCentral | date = 2007-05-29 | access-date = 2010-07-02}}</ref>) are human [[gene]]s and their [[protein]] products, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally '''breast cancer 2'''; currently '''BRCA2, DNA repair associated''') are [[gene nomenclature|maintained]] by the [[HUGO Gene Nomenclature Committee]]. One alternative symbol, [[FANCD1]], recognizes its association with the [[FANC proteins|FANC protein]] complex. [[Ortholog]]s, styled ''Brca2'' and Brca2, are common in other [[vertebrate]] species.<ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: BRCA2 coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000139618_BRCA2.xml | access-date = 2010-02-19 | archive-url = https://web.archive.org/web/20160303172228/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000139618_BRCA2.xml | archive-date = 2016-03-03 }}</ref><ref name="Ensembl">{{cite web |title=BRCA2 gene tree |url=http://www.ensembl.org/Multi/GeneTree/Image?gt=ENSGT00390000003602 |publisher=Ensembl}} May 2021</ref> ''BRCA2'' is a human [[tumor suppressor gene]]<ref name="pmid10193517">{{cite journal | vauthors = Duncan JA, Reeves JR, Cooke TG | title = BRCA1 and BRCA2 proteins: roles in health and disease | journal = Molecular Pathology | volume = 51 | issue = 5 | pages = 237–47 | date = October 1998 | pmid = 10193517 | pmc = 395646 | doi = 10.1136/mp.51.5.237 }}</ref><ref name="pmid15546503">{{cite journal | vauthors = Yoshida K, Miki Y | title = Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage | journal = Cancer Science | volume = 95 | issue = 11 | pages = 866–71 | date = November 2004 | pmid = 15546503 | doi = 10.1111/j.1349-7006.2004.tb02195.x | s2cid = 24297965 | doi-access = free | pmc = 11159131 }}</ref> (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.<ref name="CAP">{{cite web | url = http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=cap_today%2Ffeature_stories%2F0906BRCA.html&_state=maximized&_pageLabel=cntvwr | title = BRCA: What we know now | author = Check W | publisher = College of American Pathologists | date = 2006-09-01 | access-date = 2010-08-23}}</ref>

''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 [[chromosome|chromosomal]] damage with an important role in the error-free [[DNA repair|repair of DNA]] double strand breaks.<ref name= "Friedenson2007">{{cite journal | vauthors = Friedenson B | title = The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. | journal = BMC Cancer | volume = 7 | pages = 152–162 | date = August 2007 | pmid = 17683622 | pmc = 1959234 | doi = 10.1186/1471-2407-7-152 | issue=1 | doi-access = free }}</ref><ref name="scivee.tv">{{cite web | url = http://www.scivee.tv/node/6090 | title = Breast cancer genes protect against some leukemias and lymphomas | author = Friedenson B | date = 2008-06-08  | format = video | publisher = SciVee }}</ref> If ''BRCA1'' or ''BRCA2'' itself is damaged by a [[BRCA mutation|''BRCA'' mutation]], damaged DNA is not repaired properly, and this increases the risk for [[breast cancer]].<ref name="urlBreast and Ovarian Cancer Genetic Screening">{{cite web | url = http://www.pamf.org/health/guidelines/geneticscreening.html | title = Breast and Ovarian Cancer Genetic Screening | publisher = Palo Alto Medical Foundation | access-date = 2008-10-11| archive-url= https://web.archive.org/web/20081004080235/http://www.pamf.org/health/guidelines/geneticscreening.html| archive-date= 4 October 2008 | url-status= live}}</ref><ref name="pmid17683622">{{cite journal | vauthors = Friedenson B | title = The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers | journal = BMC Cancer | volume = 7 | page = 152 | year = 2007 | pmid = 17683622 | pmc = 1959234 | doi = 10.1186/1471-2407-7-152 | issue=1 | doi-access = free }}</ref> ''BRCA1'' and ''BRCA2'' have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins".  The predominant allele has a normal tumor suppressive function whereas high [[penetrance]] mutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer.<ref name="O'Donovan_2010">{{cite journal | vauthors = O'Donovan PJ, Livingston DM | title = BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair | journal = Carcinogenesis | volume = 31 | issue = 6 | pages = 961–7 | date = April 2010 | pmid = 20400477 | doi = 10.1093/carcin/bgq069 | doi-access = free }}</ref>

The ''BRCA2'' gene is located on the long (q) arm of [[chromosome 13 (human)|chromosome 13]] at position 12.3 (13q12.3).<ref name="pmid8091231">{{cite journal | vauthors = Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D | title = Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13 | journal = Science | volume = 265 | issue = 5181 | pages = 2088–90 | date = September 1994 | pmid = 8091231 | doi = 10.1126/science.8091231 | bibcode = 1994Sci...265.2088W }}</ref> The human reference ''BRCA2'' gene contains 27 exons, and the cDNA has  10,254 base pairs<ref name="EntrezGene">{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/675 | title = BRCA2 breast cancer 2, early onset [Homo sapiens] | work = EntrezGene | publisher = National Center for Biotechnology Information, U.S. National Library of Medicine }}</ref> coding for a protein of 3418 amino acids.<ref name="UniProt_P51587">{{cite web | url = https://www.uniprot.org/uniprot/P51587 | title = Breast cancer type 2 susceptibility protein - Homo sapiens (Human) | work = P51587 | publisher = UniProt }}</ref><ref name = " Williams-Jones_2002">{{cite thesis | type = Ph.D. | author = Williams-Jones B | title = Genetic testing for sale: Implications of commercial brca testing in Canada | publisher = The University of British Columbia | year = 2002 }}</ref>

== Function ==
[[File:Homologous recombinational repair of DNA double-strand damage.jpg|thumb|300px|'''Recombinational repair of DNA double-strand damage - some key steps.'''  [[Ataxia telangiectasia mutated|ATM]] (ATM) is a [[protein kinase]] that is recruited and activated by [[DNA repair#Double-strand breaks|DNA double-strand breaks]].  DNA double-strand damages also activate the [[FANC proteins|Fanconi anemia core complex]] (FANCA/B/C/E/F/G/L/M).<ref name="pmid20484397">{{cite journal |vauthors=D'Andrea AD |title=Susceptibility pathways in Fanconi's anemia and breast cancer |journal=N. Engl. J. Med. |volume=362 |issue=20 |pages=1909–19 |year=2010 |pmid=20484397 |pmc=3069698 |doi=10.1056/NEJMra0809889 }}</ref>  The FA core complex [[ubiquitin|monoubiquitinates]] the downstream targets FANCD2 and FANCI.<ref name="pmid19633289">{{cite journal |vauthors=Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME |title=The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways |journal=J. Biol. Chem. |volume=284 |issue=38 |pages=25560–8 |year=2009 |pmid=19633289 |pmc=2757957 |doi=10.1074/jbc.M109.007690 |doi-access=free }}</ref>   ATM activates (phosphorylates) [[CHEK2]] and [[FANCD2]]<ref name=Castillo>{{cite journal |vauthors=Castillo P, Bogliolo M, Surralles J |title=Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage |journal=DNA Repair (Amst.) |volume=10 |issue=5 |pages=518–25 |year=2011 |pmid=21466974 |doi=10.1016/j.dnarep.2011.02.007 }}</ref>  CHEK2 phosphorylates BRCA1.<ref name="pmid21088254">{{cite journal |vauthors=Stolz A, Ertych N, Bastians H |title=Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability |journal=Clin. Cancer Res. |volume=17 |issue=3 |pages=401–5 |year=2011 |pmid=21088254 |doi=10.1158/1078-0432.CCR-10-1215 |doi-access=free }}</ref>   Ubiquinated FANCD2 complexes with [[BRCA1]] and [[RAD51]].<ref name="pmid12239151">{{cite journal |vauthors=Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD |title=S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51 |journal=Blood |volume=100 |issue=7 |pages=2414–20 |year=2002 |pmid=12239151 |doi=10.1182/blood-2002-01-0278 |doi-access=free }}</ref>  The [[PALB2]] protein acts as a hub,<ref name="pmid24998779">{{cite journal |vauthors=Park JY, Zhang F, Andreassen PR |title=PALB2: the hub of a network of tumor suppressors involved in DNA damage responses |journal=Biochim. Biophys. Acta |volume=1846 |issue=1 |pages=263–75 |year=2014 |pmid=24998779 |pmc=4183126 |doi=10.1016/j.bbcan.2014.06.003 }}</ref> bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex [[RAD51L1|RAD51B]]-[[RAD51C]]-[[RAD51L3|RAD51D]]-[[XRCC2]] (BCDX2).  The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.<ref name=Chun>{{cite journal |vauthors=Chun J, Buechelmaier ES, Powell SN |title=Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway |journal=Mol. Cell. Biol. |volume=33 |issue=2 |pages=387–95 |year=2013 |pmid=23149936 |pmc=3554112 |doi=10.1128/MCB.00465-12 }}</ref>  [[RAD51]] plays a major role in [[homologous recombination]]al repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules.  RAD51 is involved in the search for homology and strand pairing stages of the process.]]

Although the structures of the ''[[BRCA1]]'' and ''BRCA2'' genes are very different, at least some functions are interrelated. The [[protein]]s made by both [[gene]]s are essential for repairing damaged DNA (see Figure of recombinational repair steps). BRCA2 binds the single strand DNA and directly interacts with the recombinase [[RAD51]] to stimulate<ref>{{cite journal | vauthors = Jensen RB, Carreira A, Kowalczykowski SC | title = Purified human BRCA2 stimulates RAD51-mediated recombination | journal = Nature | volume = 467 | issue = 7316 | pages = 678–83 | date = October 2010 | pmid = 20729832 | pmc = 2952063 | doi = 10.1038/nature09399 | bibcode = 2010Natur.467..678J }}</ref> and maintain <ref>{{cite journal | vauthors = Wang CX, Jimenez-Sainz J, Jensen RB, Mazin AV | title = The Post-Synaptic Function of Brca2 | journal = Scientific Reports | volume = 9 | issue = 1 | page = 4554 | date = March 2019 | pmid = 30872704 | doi = 10.1038/s41598-019-41054-y | pmc=6418147| bibcode = 2019NatSR...9.4554W }}</ref> strand invasion, a vital step of [[homologous recombination]]. The localization of RAD51 to the DNA double-strand break requires the formation of the BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2)<ref name="pmid16793542">{{cite journal | vauthors = Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM | title = Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2 | journal = Molecular Cell | volume = 22 | issue = 6 | pages = 719–29 | date = June 2006 | pmid = 16793542 | doi = 10.1016/j.molcel.2006.05.022 | doi-access = free }}</ref> can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.<ref name="Buisson_2010">{{cite journal | vauthors = Buisson R, Dion-Côté AM, Coulombe Y, Launay H, Cai H, Stasiak AZ, Stasiak A, Xia B, Masson JY | title = Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination | journal = Nature Structural & Molecular Biology | volume = 17 | issue = 10 | pages = 1247–54 | date = October 2010 | pmid = 20871615 | pmc = 4094107 | doi = 10.1038/nsmb.1915 }}</ref> 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 has been shown to possess a crucial role in protection from the [[Mre11-Rad50-Xrs2|MRE11]]-dependent nucleolytic degradation of the [[reversed forks]] that are forming during [[DNA replication]] fork stalling (caused by obstacles such as mutations, intercalating agents etc.).<ref>{{cite journal | vauthors = Mijic S, Zellweger R, Chappidi N, Berti M, Jacobs K, Mutreja K, Ursich S, Ray Chaudhuri A, Nussenzweig A, Janscak P, Lopes M | title = Replication fork reversal triggers fork degradation in BRCA2-defective cells | language = En | journal = Nature Communications | volume = 8 | issue = 1 | page = 859 | date = October 2017 | pmid = 29038466 | pmc = 5643541 | doi = 10.1038/s41467-017-01164-5 | bibcode = 2017NatCo...8..859M }}</ref>

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

== Clinical significance ==
[[File:BRCA1 and BRCA2 mutations and absolute cancer risk.jpg|thumb|310px|Absolute risk of cancers in [[BRCA1]] or BRCA2 mutation.<ref name="Petrucelli_2016">{{cite book | vauthors = Petrucelli N, Daly MB, Pal T | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A | chapter = BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer | title = GeneReviews | publisher = University of Washington, Seattle | orig-date = September 1998 | date = December 2016 | pmid = 20301425 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1247/ }}</ref>]]
{{Further|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 fix DNA damage that occurs throughout the genome.  As a result, there is an increase in mutations due to error-prone [[DNA repair#Translesion synthesis|translesion synthesis]] past un-repaired DNA damage, and some of these mutations 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.<ref name="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable |journal=Molecular Medicine | volume = 18 | issue = 9 | pages = 1327–37 | year = 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref>

In addition to breast cancer in men and women, mutations in ''BRCA2'' also lead to an increased risk of [[ovarian cancer|ovarian]], [[Fallopian tube|uterine tube]], [[prostate cancer|prostate]] and [[pancreatic cancer]]. 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{{which|date=July 2024}} have also been seen in certain families with ''BRCA2'' mutations.{{cn|date=July 2024}}

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.<ref>{{cite web | url = http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page2| title = High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes | publisher=National Cancer Institute | access-date = 7 December 2012}}</ref>

== History ==
The BRCA2 gene was discovered in 1994 by a multi-institutional team of scientists, led by researchers at The Institute of Cancer Research, London.<ref>{{cite journal | vauthors = Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G | title = Identification of the breast cancer susceptibility gene BRCA2 | journal = Nature | volume = 378 | issue = 6559 | pages = 789–792 | year = 1995 | pmid = 8524414 | doi = 10.1038/378789a0 | s2cid = 4346791 | bibcode = 1995Natur.378..789W }}</ref><ref name="pmid8091231"/><ref>[http://scienceblog.cancerresearchuk.org/2012/02/29/high-impact-science-tracking-down-the-brca-genes-part-2/ High-Impact Science: Tracking down the BRCA genes (Part 2)] {{Webarchive|url=https://web.archive.org/web/20120303055450/https://scienceblog.cancerresearchuk.org/2012/02/29/high-impact-science-tracking-down-the-brca-genes-part-2/ |date=2012-03-03 }} - Cancer Research UK science blog, 2012</ref> In 1996, [[Kenneth Offit]] and his research group at [[Memorial Sloan Kettering Cancer Center]] successfully identified the most common mutation on the gene associated with breast and ovarian cancer among individuals of [[Ashkenazi Jewish]] ancestry.<ref name=":1">{{cite web |title=Kenneth Offit &#124; Breast Cancer Research Foundation &#124; BCRF |date=23 June 2014 |url=http://www.bcrfcure.org/researchers/kenneth-offit |access-date=2015-07-16 |publisher=Bcrfcure.org |archive-date=2015-07-17 |archive-url=https://web.archive.org/web/20150717133312/http://www.bcrfcure.org/researchers/kenneth-offit }}</ref><ref>{{cite news |date=2003-02-25 |title=A revolution at 50; kenneth offit |newspaper=[[The New York Times]] |url=https://www.nytimes.com/2003/02/25/science/a-revolution-at-50-kenneth-offit.html |access-date=2015-07-02 |issn=0362-4331}}</ref><ref name=":0">{{cite web |title=20 Years of Progress in Understanding Breast Cancer |url=https://www.mskcc.org/sites/default/files/node/28114/images/hereditary-breast-cancer-timeline.jpg |access-date=2015-07-17 |publisher=Mskcc.org |format=JPG}}</ref><ref>{{Cite news | vauthors = Kolata G |date=1996-10-02 |title=2d Breast Cancer Gene Found in Jewish Women |newspaper=[[The New York Times]] |url=https://www.nytimes.com/1996/10/02/us/2d-breast-cancer-gene-found-in-jewish-women.html |access-date=2015-07-07 |issn=0362-4331}}</ref>

The gene was first cloned by scientists at [[Myriad Genetics]], Endo Recherche, Inc., HSC Research & Development Limited Partnership, and the [[University of Pennsylvania]].<ref name=492Patent>{{ cite patent | country = US | number = 5837492 | status = patent | title = Chromosome 13-linked breast cancer susceptibility gene | gdate = 1998-11-17 | fdate =  1996-04-29 | inventor =  Tavtigian SV, Kamb A, Simard J, Couch F, Rommens JM, Weber BL | assign1 = Myriad Genetics, Inc., Endo Recherche, Inc., HSC Research & Development Limited Partnership, Trustees of the University of Pennsylvania }}</ref>

Methods to diagnose the likelihood of a patient with mutations in [[BRCA1]] and '''BRCA2''' getting cancer were covered by [[Biological patent|patents]] owned or controlled by [[Myriad Genetics]].<ref name="US_5747282">{{Ref patent  | country = US | number = 5747282  | status = patent  | title = 7Q-linked breast and ovarian cancer susceptibility gene  | pubdate =  | gdate = 1998-05-05  | fdate = 1995-06-07  | pridate = | inventor = Skolnick HS, Goldgar DE, Miki Y, Swenson J, Kamb A, Harshman KD, Shattuck-Eidens DM, Tavtigian SV, Wiseman RW, Futreal PA  | assign1 = Myriad Genetics, Inc., The United States of America as represented by the Secretary of Health and Human Services, | assign2 = University of Utah Research Foundation }}</ref><ref name="US_5837492">{{ cite patent | country = US | number = 5837492 | status = patent | title = Chromosome 13-linked breast cancer susceptibility gene | gdate = 1998-11-17 | fdate =  1996-04-29 | inventor = Tavtigian SV, Kamb A, Simard J, Couch F, Rommens JM, Weber BL | assign1 = Myriad Genetics, Inc., Endo Recherche, Inc., HSC Research & Development Limited Partnership, Trustees of the University of Pennsylvania }}</ref> Myriad's business model of exclusively offering the diagnostic test led from Myriad's beginnings as a startup in 1994 to its being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012;<ref name=MyriadInvestorPage>[http://investor.myriad.com/index.cfm Myriad Investor Page—see "Myriad at a glance"] {{Webarchive|url=https://web.archive.org/web/20121018224334/http://investor.myriad.com/index.cfm |date=2012-10-18 }} accessed October 2012</ref> it also led to controversy over high test prices and the unavailability of second opinions from other diagnostic labs, which in turn led to the landmark ''[[Association for Molecular Pathology v. Myriad Genetics]]'' lawsuit.<ref name="SchwartzNYTimes">{{cite web | url = https://www.nytimes.com/2009/05/13/health/13patent.html | title = Cancer Patients Challenge the Patenting of a Gene | author = Schwartz J  | date = 2009-05-12 | work = Health | publisher = New York Times }}</ref>

== Germline mutations and founder effect ==
All germline 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.<ref name="Lacroix2005">{{cite journal | vauthors = Lacroix M, Leclercq G | title = The "portrait" of hereditary breast cancer | journal = Breast Cancer Research and Treatment | volume = 89 | issue = 3 | pages = 297–304 | year = 2005 | pmid = 15754129 | doi = 10.1007/s10549-004-2172-4 | s2cid = 23327569 }}</ref> 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.<ref name="Thorlacius1996">{{cite journal | vauthors = Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjörd JE | title = A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes | journal = Nature Genetics | volume = 13 | issue = 1 | pages = 117–119 | year = 1996 | pmid = 8673089 | doi = 10.1038/ng0596-117 | s2cid = 8443452 }}</ref><ref name="Thorlacius1997">{{cite journal | vauthors = Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjörd JE | title = Study of a single BRCA2 mutation with high carrier frequency in a small population | journal = American Journal of Human Genetics | volume = 60 | issue = 5 | pages = 1079–1085 | year = 1997 | pmid = 9150155 | pmc = 1712443 }}</ref> 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.

{{Dynamic list}}

{| class="wikitable"
|-
! Population or subgroup !! BRCA2 mutation(s)<ref name="Lacroix2005"/><ref name="denDunnen2000">{{cite journal | vauthors = den Dunnen JT, Antonarakis SE | title = Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. | journal = Human Mutation | volume = 15 | issue = 1 | pages = 7–12 | year = 2000 | pmid = 10612815 | doi = 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N | doi-access = free }}</ref>!! Reference(s)
|-
| Ashkenazi Jewish || 6174delT ||<ref name="Neuhausen1996">{{cite journal | vauthors = Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, Hampel H, Borgen P, Brown K, Skolnick M, Shattuck-Eidens D, Jhanwar S, Goldgar D, Offit K | title = Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer | journal = Nature Genetics | volume = 13 | issue = 1 | pages = 126–128 | year = 1996 | pmid = 8673092 | doi = 10.1038/ng0596-126 | s2cid = 11909356 }}</ref>
|-
| Dutch || 5579insA ||<ref name=" Verhoog ">{{cite journal | vauthors = Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H | title = Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families | journal = European Journal of Cancer | volume = 37 | issue = 16 | pages = 2082–2090 | year = 2001 | pmid = 11597388 | doi = 10.1016/S0959-8049(01)00244-1 }}</ref>
|-
| Finns || 8555T>G, 999del5, IVS23-2A>G ||<ref name="Huusko">{{cite journal | vauthors = Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R | title = Evidence of founder mutations in Finnish BRCA1 and BRCA2 families | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1544–1548 | year = 1998 | pmid = 9585608 | pmc = 1377159 | doi = 10.1086/301880 }}</ref><ref name="Paakkonen">{{cite journal | vauthors = Pääkkönen K, Sauramo S, Sarantaus L, Vahteristo P, Hartikainen A, Vehmanen P, Ignatius J, Ollikainen V, Kääriäinen H, Vauramo E, Nevanlinna H, Krahe R, Holli K, Kere J | title = Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population | journal = Genetic Epidemiology | volume = 20 | issue = 2 | pages = 239–246 | year = 2001 | pmid = 11180449 | doi = 10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y | s2cid = 41804152 }}</ref>
|-
| French Canadians || 8765delAG, 3398delAAAAG ||<ref name="Tonin1999">{{cite journal | vauthors = Tonin PN, Mes-Masson AM, Narod SA, Ghadirian P, Provencher D | title = Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history | journal = Clinical Genetics | volume = 55 | issue = 5 | pages = 318–324 | year = 1999 | pmid = 10422801 | doi = 10.1034/j.1399-0004.1999.550504.x | s2cid = 23931343 }}</ref><ref name="Oros2006">{{cite journal | vauthors = Oros KK, Leblanc G, Arcand SL, Shen Z, Perret C, Mes-Masson AM, Foulkes WD, Ghadirian P, Provencher D, Tonin PN | title = Haplotype analysis suggests common founders in carriers of recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families | journal = BMC Medical Genetics | volume = 7 | issue = 23 | page = 23 | year = 2006 | pmid = 16539696 | doi = 10.1186/1471-2350-7-23 | pmc=1464093 | doi-access = free }}</ref><ref name="Tonin2006">{{cite journal | vauthors = Tonin PN | title = The limited spectrum of pathogenic BRCA1 and BRCA2 mutations in the French Canadian breast and breast-ovarian cancer families, a founder population of Quebec, Canada | journal = Bull Cancer | volume = 93 | issue = 9 | pages = 841–846 | year = 2006 | pmid = 16980226 }}</ref>
|-
| Hungarians || 9326insA ||<ref name=" VanDerLooij2000 ">{{cite journal | vauthors = Van Der Looij M, Szabo C, Besznyak I, Liszka G, Csokay B, Pulay T, Toth J, Devilee P, King MC, Olah E | title = Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary | journal = International Journal of Cancer | volume = 86 | issue = 5 | pages = 737–740 | year = 2000 | pmid = 10797299 | doi = 10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1 | s2cid = 25394976 | doi-access = free }}</ref>
|-
| Icelanders || 999del5 ||<ref name="Thorlacius1996"/><ref name="Thorlacius1997"/>
|-
| Italians || 8765delAG ||<ref name="Pisano2000">{{cite journal | vauthors = Pisano M, Cossu A, Persico I, Palmieri G, Angius A, Casu G, Palomba G, Sarobba MG, Rocca PC, Dedola MF, Olmeo N, Pasca A, Budroni M, Marras V, Pisano A, Farris A, Massarelli G, Pirastu M, Tanda F | title = Identification of a founder BRCA2 mutation in Sardinia | journal = British Journal of Cancer | volume = 82 | issue = 3 | pages = 553–559 | year = 2000 | pmid = 10682665 | pmc = 2363305 | doi = 10.1054/bjoc.1999.0963 }}</ref>
|-
| Northern Irish || 6503delTT ||<ref name="TSNI2003">{{cite journal | vauthors = Anderson E, Anderson V, Baty D, Beers C, Black D, Black R, Boyd M, Bradley A, Brewster D, Brown I, Milner BJ | collaboration = Scottish/Northern Irish BRCAI/BRCA2 Consortium | title = BRCA1 and BRCA2 mutations in Scotland and Northern Ireland | journal = British Journal of Cancer | volume = 88 | issue = 8 | pages = 1256–1262 | year = 2003 | pmid = 12698193 | pmc = 2747571 | doi = 10.1038/sj.bjc.6600840 }}</ref>
|-
| Pakistanis || 3337C>T ||<ref name="Liede2002">{{cite journal | vauthors = Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA | title = Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan | journal = American Journal of Human Genetics | volume = 71 | issue = 3 | pages = 595–606 | year = 2002 | pmid = 12181777 | pmc = 379195 | doi = 10.1086/342506 }}</ref>
|-
| Scottish || 6503delTT ||<ref name="TSNI2003"/>
|-
| Scottish || c.517-2A>G ||<ref name=" Kerr2024 ">{{cite medrxiv | vauthors = Kerr SM, Klaric L, Muckian MD, Cowan E, Snadden L, Tzoneva G, Shuldiner AR, Miedzybrodzka Z, Wilson JF | title = Two founder variants account for over 90% of pathogenic BRCA alleles in Orkney and Shetland | year = 2024 | medrxiv = 10.1101/2024.04.03.24305239  }}</ref>
|-
| Slovenians || IVS16-2A>G ||<ref name="Krajc2002">{{cite journal | vauthors = Krajc M, De Grève J, Goelen G, Teugels E | title = BRCA2 founder mutation in Slovenian breast cancer families | journal = European Journal of Human Genetics | volume = 10 | issue = 12 | pages = 879–882 | year = 2002 | pmid = 12461697 | doi = 10.1038/sj.ejhg.5200886 | doi-access = free }}</ref>
|-
| Spanish || 3034delAAAC(codon936), 9254del5 ||<ref name="Osorio1998">{{cite journal | vauthors = Osorio A, Robledo M, Martínez B, Cebrián A, San Román JM, Albertos J, Lobo F, Benítez J | title =   Molecular analysis of the BRCA2 gene in 16 breast/ovarian cancer Spanish families| doi = 10.1111/j.1399-0004.1998.tb03717.x | pmid = 9761393 | volume=54 | issue =   2| year=1998 | journal=Clin. Genet. | pages=142–7| s2cid = 30388365}}</ref>
|-
| Swedish || 4486delG ||<ref name="Neuhausen2000">{{cite journal | vauthors = Neuhausen SL | title = Founder populations and their uses for breast cancer genetics | journal = Cancer Research | volume = 2 | issue = 2 | pages = 77–81 | year = 2000 | pmid = 11250694 | pmc = 139426 | doi = 10.1186/bcr36 | doi-access = free }}</ref>
|}

==Meiosis==

In the plant ''[[Arabidopsis thaliana]]'', loss of the ''BRCA2'' homolog ''AtBRCA2'' causes severe defects in both male [[meiosis]] and in the development of the female [[gametocyte]].<ref name=Seeliger>{{cite journal |vauthors=Seeliger K, Dukowic-Schulze S, Wurz-Wildersinn R, Pacher M, Puchta H |title=BRCA2 is a mediator of RAD51- and DMC1-facilitated homologous recombination in Arabidopsis thaliana |journal=New Phytol. |volume=193 |issue=2 |pages=364–75 |year=2012 |pmid=22077663 |doi=10.1111/j.1469-8137.2011.03947.x |doi-access=free }}</ref>  AtBRCA2 protein is required for proper localization of the [[synaptonemal complex]] protein AtZYP1 and the recombinases AtRAD51 and AtDMC1.  Furthermore, AtBRCA2 is required for proper meiotic synapsis.  Thus AtBRCA2 is likely important for meiotic recombination.  It appears that AtBRCA2 acts during meiosis to control the single-strand invasion steps mediated by AtRAD51 and AtDMC1 occurring during meiotic [[homologous recombination]]al repair of DNA damages.<ref name=Seeliger />

Homologs of BRCA2 are also essential for meiosis in the fungus ''[[Ustilago maydis]]'',<ref name="pmid12408834">{{cite journal |vauthors=Kojic M, Kostrub CF, Buchman AR, Holloman WK |title=BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis |journal=Mol. Cell |volume=10 |issue=3 |pages=683–91 |year=2002 |pmid=12408834 |doi= 10.1016/s1097-2765(02)00632-9|doi-access=free }}</ref> the worm ''[[Caenorhabditis elegans]]'',<ref name="pmid18779660">{{cite journal |vauthors=Ko E, Lee J, Lee H |title=Essential role of brc-2 in chromosome integrity of germ cells in C. elegans |journal=Mol. Cells |volume=26 |issue=6 |pages=590–4 |year=2008 |doi=10.1016/S1016-8478(23)14041-6 |pmid=18779660 |doi-access=free }}</ref><ref name="pmid15798199">{{cite journal |vauthors=Martin JS, Winkelmann N, Petalcorin MI, McIlwraith MJ, Boulton SJ |title=RAD-51-dependent and -independent roles of a Caenorhabditis elegans BRCA2-related protein during DNA double-strand break repair |journal=Mol. Cell. Biol. |volume=25 |issue=8 |pages=3127–39 |year=2005 |pmid=15798199 |pmc=1069622 |doi=10.1128/MCB.25.8.3127-3139.2005 }}</ref> and the fruitfly ''[[Drosophila melanogaster]]''.<ref name="pmid18266476">{{cite journal |vauthors=Klovstad M, Abdu U, Schüpbach T |title=Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint |journal=PLOS Genet. |volume=4 |issue=2 |article-number=e31 |year=2008 |pmid=18266476 |pmc=2233675 |doi=10.1371/journal.pgen.0040031 |doi-access=free }}</ref>

Mice that produce truncated versions of BRCA2 are viable but sterile.<ref name="pmid9398843">{{cite journal |vauthors=Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E, Tybulewicz VL, Ashworth A |title=Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation |journal=Nat. Genet. |volume=17 |issue=4 |pages=423–30 |year=1997 |pmid=9398843 |doi=10.1038/ng1297-423 |s2cid=42462448 }}</ref>  BRCA2 mutant rats have a phenotype of growth inhibition and sterility in both sexes.<ref name="pmid16964288">{{cite journal |vauthors=Cotroneo MS, Haag JD, Zan Y, Lopez CC, Thuwajit P, Petukhova GV, Camerini-Otero RD, Gendron-Fitzpatrick A, Griep AE, Murphy CJ, Dubielzig RR, Gould MN |title=Characterizing a rat Brca2 knockout model |journal=Oncogene |volume=26 |issue=11 |pages=1626–35 |year=2007 |pmid=16964288 |doi=10.1038/sj.onc.1209960 |doi-access=free }}</ref>  Aspermatogenesis in these mutant rats is due to a failure of homologous chromosome synapsis during meiosis.

===BRC repeat sequences===

''[[DMC1 (gene)|DMC1]]'' (DNA meiotic recombinase 1) is a [[meiosis]] specific homolog of ''[[RAD51]]'' that mediates strand exchange during [[homologous recombination]]al repair.  DMC1 promotes the formation of DNA strand invasion products (joint molecules) between homologous DNA molecules.  Human DMC1 interacts directly with each of a series of repeat sequences in the BRCA2 protein (called BRC repeats) that stimulate joint molecule formation by DMC1.<ref name=Martinez>{{cite journal |vauthors=Martinez JS, von Nicolai C, Kim T, Ehlén Å, Mazin AV, Kowalczykowski SC, Carreira A |title=BRCA2 regulates DMC1-mediated recombination through the BRC repeats |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=113 |issue=13 |pages=3515–20 |year=2016 |pmid=26976601 |pmc=4822569 |doi=10.1073/pnas.1601691113 |bibcode=2016PNAS..113.3515M |doi-access=free }}</ref>  BRC repeats conform to a motif consisting of a sequence of about 35 highly conserved amino acids that are present at least once in all BRCA2-like proteins.  The BRCA2 BRC repeats stimulate joint molecule formation by promoting the interaction of single-stranded DNA (ssDNA) with DMC1.<ref name=Martinez />  The ssDNA complexed with DMC1 can pair with homologous ssDNA from another chromosome during the synopsis stage of [[meiosis]] to form a joint molecule, a central step in [[homologous recombination]]. Thus the BRC repeat sequences of BRCA2 appear to play a key role in recombinational repair of DNA damages during meiotic recombination.

Overall, it appears that homologous recombination during meiosis functions to repair DNA damages,<ref>{{Cite journal |last=Prakash |first=Rohit |last2=Zhang |first2=Yu |last3=Feng |first3=Weiran |last4=Jasin |first4=Maria |date=2015-04-01 |title=Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC4382744/ |journal=Cold Spring Harbor Perspectives in Biology |volume=7 |issue=4 |article-number=a016600 |doi=10.1101/cshperspect.a016600 |issn=1943-0264 |pmc=4382744 |pmid=25833843}}</ref> and that BRCA2 plays a key role in performing this function.

==Neurogenesis==

BRCA2 is required in the mouse for [[neurogenesis]] and suppression of [[medulloblastoma]].<ref name=Frappart>{{cite journal |vauthors=Frappart PO, Lee Y, Lamont J, McKinnon PJ |title=BRCA2 is required for neurogenesis and suppression of medulloblastoma |journal=EMBO J. |volume=26 |issue=11 |pages=2732–42 |year=2007 |pmid=17476307 |pmc=1888666 |doi=10.1038/sj.emboj.7601703 }}</ref>  ''BRCA2'' loss profoundly affects neurogenesis, particularly during embryonic and postnatal neural development.  These neurological defects arise from DNA damage.<ref name=Frappart />

==Epigenetic control==

Epigenetic alterations in expression of BRCA2 (causing over-expression or under-expression) are very frequent in sporadic cancers (see Table below) while mutations in BRCA2 are rarely found.<ref name="pmid8640236">{{cite journal |vauthors=Teng DH, Bogden R, Mitchell J, Baumgard M, Bell R, Berry S, Davis T, Ha PC, Kehrer R, Jammulapati S, Chen Q, Offit K, Skolnick MH, Tavtigian SV, Jhanwar S, Swedlund B, Wong AK, Kamb A |title=Low incidence of BRCA2 mutations in breast carcinoma and other cancers |journal=Nat. Genet. |volume=13 |issue=2 |pages=241–4 |year=1996 |pmid=8640236 |doi=10.1038/ng0696-241 |s2cid=9831745 }}</ref><ref name="pmid8640237">{{cite journal |vauthors=Miki Y, Katagiri T, Kasumi F, Yoshimoto T, Nakamura Y |title=Mutation analysis in the BRCA2 gene in primary breast cancers |journal=Nat. Genet. |volume=13 |issue=2 |pages=245–7 |year=1996 |pmid=8640237 |doi=10.1038/ng0696-245 |s2cid=3203046 }}</ref><ref name="pmid8640235">{{cite journal |vauthors=Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, Seal S, Barfoot R, Collins N, Bignell G, Patel S, Hamoudi R, Larsson C, Wiseman RW, Berchuck A, Iglehart JD, Marks JR, Ashworth A, Stratton MR, Futreal PA |title=BRCA2 mutations in primary breast and ovarian cancers |journal=Nat. Genet. |volume=13 |issue=2 |pages=238–40 |year=1996 |pmid=8640235 |doi=10.1038/ng0696-238 |s2cid=26808443 }}</ref>

In non-small cell lung cancer, BRCA2 is epigenetically repressed by hypermethylation of the promoter.<ref name=Lee>{{cite journal |vauthors=Lee MN, Tseng RC, Hsu HS, Chen JY, Tzao C, Ho WL, Wang YC |title=Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer |journal=Clin. Cancer Res. |volume=13 |issue=3 |pages=832–8 |year=2007 |pmid=17289874 |doi=10.1158/1078-0432.CCR-05-2694 |doi-access=free }}</ref>  In this case, promoter hypermethylation is significantly associated with low [[Messenger RNA|mRNA]] expression and low protein expression but not with loss of heterozygosity of the gene.

In sporadic ovarian cancer, an opposite effect is found.  BRCA2 promoter and 5'-UTR regions have relatively few or no methylated CpG dinucleotides in the tumor DNA compared with that of non-tumor DNA, and a significant correlation is found between hypomethylation and a >3-fold over-expression of BRCA2.<ref name=Chan>{{cite journal |vauthors=Chan KY, Ozçelik H, Cheung AN, Ngan HY, Khoo US |title=Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer |journal=Cancer Res. |volume=62 |issue=14 |pages=4151–6 |year=2002 |pmid=12124354 }}</ref>  This indicates that hypomethylation of the BRCA2 promoter and [[Five prime untranslated regions|5'-UTR regions]] leads to over-expression of BRCA2 mRNA.

One report indicated some epigenetic control of BRCA2 expression by the [[microRNA]]s miR-146a and miR-148a.<ref name="pmid25537514">{{cite journal |vauthors=Gu Y, Zhang M, Peng F, Fang L, Zhang Y, Liang H, Zhou W, Ao L, Guo Z |title=The BRCA1/2-directed miRNA signature predicts a good prognosis in ovarian cancer patients with wild-type BRCA1/2 |journal=Oncotarget |volume=6 |issue=4 |pages=2397–406 |year=2015 |pmid=25537514 |pmc=4385859 |doi=10.18632/oncotarget.2963 }}</ref>

==BRCA2 expression in cancer==

In [[eukaryote]]s, BRCA2 protein has an important role in homologous recombinational repair. In mice and humans, BRCA2 primarily mediates orderly assembly of RAD51 on single-stranded (ss) DNA, the form that is active for homologous pairing and strand invasion.<ref name=Holloman>{{cite journal |vauthors=Holloman WK |title=Unraveling the mechanism of BRCA2 in homologous recombination |journal=Nat. Struct. Mol. Biol. |volume=18 |issue=7 |pages=748–54 |year=2011 |pmid=21731065 |pmc=3647347 |doi=10.1038/nsmb.2096 }}</ref> BRCA2 also redirects RAD51 from double-stranded DNA and prevents dissociation from ssDNA.<ref name=Holloman />  In addition, the four [[Homology (biology)#Paralogy|paralogs]] of [[RAD51]], consisting of RAD51B ([[RAD51L1]]), RAD51C (RAD51L2), RAD51D ([[RAD51L3]]), [[XRCC2]] form a complex called the BCDX2 complex (see Figure: Recombinational repair of DNA). This complex participates in RAD51 recruitment or stabilization at damage sites.<ref name="Chun"/>  The BCDX2 complex appears to act by facilitating the assembly or stability of the [[RAD51#Function|RAD51 nucleoprotein filament]].  RAD51 catalyses strand transfer between a broken sequence and its undamaged homologue to allow re-synthesis of the damaged region (see [[Homologous recombination#Models|homologous recombination models]]).

Some studies of cancers report over-expressed ''BRCA2'' whereas other studies report under-expression of ''BRCA2''.  At least two reports found over-expression in some sporadic breast tumors and under-expression in other sporadic breast tumors.<ref name=Lidereau>{{cite journal |vauthors=Bièche I, Noguès C, Lidereau R |title=Overexpression of BRCA2 gene in sporadic breast tumours |journal=Oncogene |volume=18 |issue=37 |pages=5232–8 |year=1999 |pmid=10498873 |doi=10.1038/sj.onc.1202903 |doi-access=free }}</ref><ref name=Hedau>{{cite journal |vauthors=Hedau S, Batra M, Singh UR, Bharti AC, Ray A, Das BC |title=Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer |journal=J Cancer Res Ther |volume=11 |issue=1 |pages=158–63 |year=2015 |pmid=25879355 |doi=10.4103/0973-1482.140985 |doi-access=free }}</ref> (see Table).

Many cancers have epigenetic deficiencies in various DNA repair genes (see [[Cancer epigenetics#Frequencies of epimutations in DNA repair genes|Frequencies of epimutations in DNA repair genes in cancers]]).  These repair deficiencies likely cause increased unrepaired DNA damages. The over-expression of ''BRCA2'' seen in many cancers may reflect compensatory ''BRCA2'' over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages.  Egawa et al.<ref name=Egawa>{{cite journal |vauthors=Egawa C, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S |title=High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients |journal=Int. J. Cancer |volume=98 |issue=6 |pages=879–82 |year=2002 |pmid=11948466 |doi= 10.1002/ijc.10231|s2cid=9083282 |doi-access=free }}</ref> suggest that increased expression of BRCA2 can be explained by the genomic instability frequently seen in cancers, which induces BRCA2 mRNA expression due to an increased need for BRCA2 for DNA repair.

Under-expression of ''BRCA2'' would itself lead to increased unrepaired DNA damages.  Replication errors past these damages (see [[DNA repair#Translesion synthesis|translesion synthesis]]) would lead to increased mutations and cancer.

{| class="wikitable sortable"
|+ ''BRCA2'' expression in sporadic cancers
! Cancer !!Over or Under expression !!Frequency of altered expression!!Evaluation method !!Ref.
|-
|Sporadic ovarian cancer||Over-expression||80%||messenger RNA ||<ref name=Chan />
|-
|Sporadic ovarian cancer||Under-expression||42%||immunohistochemistry ||<ref name=Swisher>{{cite journal |vauthors=Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, Welcsh P |title=Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas |journal=Mol. Cancer |volume=8 |issue= 1|page=48 |year=2009 |pmid=19602291 |pmc=2719582 |doi=10.1186/1476-4598-8-48 |doi-access=free }}</ref>
|-
|(recurrent cancer in study above)||Increased-expression||71%||immunohistochemistry ||<ref name=Swisher />
|-
|Non-small cell lung cancer||Under-expression||34%||immunohistochemistry ||<ref name=Lee />
|-
|Breast cancer||Over-expression||66%||messenger RNA ||<ref name=Egawa />
|-
|Breast cancer||Over-expression||20%||messenger RNA ||<ref name=Lidereau />
|-
|(same study as above)||Under-expression||11%||messenger RNA ||<ref name=Lidereau />
|-
|Breast cancer||Over-expression||30%||immunohistochemistry ||<ref name=Hedau />
|-
|(same study as above)||Under-expression||30%||immunohistochemistry ||<ref name=Hedau />
|-
|Triple negative breast cancer||Under-expression||90%||immunohistochemistry ||<ref name="pmid26259780">{{cite journal |vauthors=Thike AA, Tan PH, Ikeda M, Iqbal J |title=Increased ID4 expression, accompanied by mutant p53 accumulation and loss of BRCA1/2 proteins in triple-negative breast cancer, adversely affects survival |journal=Histopathology |volume=68 |issue=5 |pages=702–12 |year=2016 |pmid=26259780 |doi=10.1111/his.12801 |s2cid=3566545 }}</ref>
|}

== Interactions ==

BRCA2 has been shown to [[protein–protein interaction|interact]] with
{{div col|colwidth=20em}}
* [[BRE (gene)|BRE]],<ref name=pmid14636569>{{cite journal | vauthors = Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK, Shiekhattar R | title = Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair | journal = Mol. Cell | volume = 12 | issue = 5 | pages = 1087–99 | date = November 2003 | pmid = 14636569 | doi = 10.1016/S1097-2765(03)00424-6 | doi-access = free }}</ref>
* [[BARD1]],<ref name=pmid14636569/><ref name=pmid19176389>{{cite journal | vauthors = Ryser S, Dizin E, Jefford CE, Delaval B, Gagos S, Christodoulidou A, Krause KH, Birnbaum D, Irminger-Finger I | title = Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1beta scaffolds Aurora B and BRCA2 | journal = Cancer Res. | volume = 69 | issue = 3 | pages = 1125–34 | date = February 2009 | pmid = 19176389 | doi = 10.1158/0008-5472.CAN-08-2134 | doi-access = free }}</ref>
* [[BCCIP]],<ref name=pmid11313963/>
* [[BRCA1]],<ref name=pmid14636569/><ref name=pmid11477095/><ref name=pmid9774970/><ref name=pmid14499622>{{cite journal | vauthors = Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA | title = Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport | journal = Exp. Cell Res. | volume = 289 | issue = 2 | pages = 211–21 | date = October 2003 | pmid = 14499622 | doi = 10.1016/S0014-4827(03)00261-1 }}</ref>
* [[BRCC3]],<ref name=pmid14636569/>
* [[BUB1B]],<ref name=pmid10749118>{{cite journal | vauthors = Futamura M, Arakawa H, Matsuda K, Katagiri T, Saji S, Miki Y, Nakamura Y | title = Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1 | journal = Cancer Res. | volume = 60 | issue = 6 | pages = 1531–5 | date = March 2000 | pmid = 10749118 }}</ref>
* [[CREB-binding protein|CREBBP]],<ref name="pmid19578754">{{cite journal | vauthors = Siddique H, Rao VN, Reddy ES | title = CBP-mediated post-translational N-glycosylation of BRCA2 | journal = Int J Oncol | volume = 35 | issue = 2 | pages = 16387–91 | date = August 2009 | pmid = 19578754 | doi = 10.3892/ijo_00000351 | doi-access = free }}</ref>
* [[C11orf30]],<ref name=pmid14651845>{{cite journal | vauthors = Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C, Kouzarides T | title = EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer | journal = Cell | volume = 115 | issue = 5 | pages = 523–35 | date = November 2003 | pmid = 14651845 | doi = 10.1016/S0092-8674(03)00930-9 | s2cid = 18911371 | doi-access = free }}</ref>
* [[FANCD2]],<ref name=pmid15199141>{{cite journal | vauthors = Wang X, Andreassen PR, D'Andrea AD | title = Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin | journal = Mol. Cell. Biol. | volume = 24 | issue = 13 | pages = 5850–62 | date = July 2004 | pmid = 15199141 | pmc = 480901 | doi = 10.1128/MCB.24.13.5850-5862.2004 }}</ref><ref name=pmid15115758>{{cite journal | vauthors = Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG | title = Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways | journal = Hum. Mol. Genet. | volume = 13 | issue = 12 | pages = 1241–8 | date = June 2004 | pmid = 15115758 | doi = 10.1093/hmg/ddh135 | doi-access = free }}</ref><ref name=pmid18263878>{{cite journal | vauthors = Hejna J, Holtorf M, Hines J, Mathewson L, Hemphill A, Al-Dhalimy M, Olson SB, Moses RE | title = Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway | journal = J. Biol. Chem. | volume = 283 | issue = 15 | pages = 9844–51 | date = April 2008 | pmid = 18263878 | pmc = 2398728 | doi = 10.1074/jbc.M709076200 | doi-access = free }}</ref>
* [[FANCG]],<ref name=pmid12915460>{{cite journal | vauthors = Hussain S, Witt E, Huber PA, Medhurst AL, Ashworth A, Mathew CG | title = Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1 | journal = Hum. Mol. Genet. | volume = 12 | issue = 19 | pages = 2503–10 | date = October 2003 | pmid = 12915460 | doi = 10.1093/hmg/ddg266 | doi-access = free }}</ref>
* [[Filamin|FLNA]],<ref name=pmid11602572>{{cite journal | vauthors = Yuan Y, Shen Z | title = Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response | journal = J. Biol. Chem. | volume = 276 | issue = 51 | pages = 48318–24 | date = December 2001 | pmid = 11602572 | doi = 10.1074/jbc.M102557200 | doi-access = free }}</ref>
* [[HMG20B]],<ref name=pmid11207365>{{cite journal | vauthors = Marmorstein LY, Kinev AV, Chan GK, Bochar DA, Beniya H, Epstein JA, Yen TJ, Shiekhattar R | title = A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression | journal = Cell | volume = 104 | issue = 2 | pages = 247–57 | date = January 2001 | pmid = 11207365 | doi = 10.1016/S0092-8674(01)00209-4 | s2cid = 5822368 | doi-access = free }}</ref><ref name=pmid12032298>{{cite journal | vauthors = Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R | title = A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes | journal = [[PNAS|Proc. Natl. Acad. Sci. U.S.A.]] | volume = 99 | issue = 11 | pages = 7420–5 | date = May 2002 | pmid = 12032298 | pmc = 124246 | doi = 10.1073/pnas.112008599 | bibcode = 2002PNAS...99.7420H | doi-access = free }}</ref>
* [[P53]],<ref name=pmid14636569/><ref name=pmid9811893/>
* [[PALB2]],<ref name="pmid16793542"/><ref name="entrez">{{cite web | title = Entrez Gene: PALB2 partner and localizer of BRCA2| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=79728}}</ref>
* [[PCAF]],<ref name=pmid12815053/><ref name=pmid9824164>{{cite journal | vauthors = Fuks F, Milner J, Kouzarides T | title = BRCA2 associates with acetyltransferase activity when bound to P/CAF | journal = Oncogene | volume = 17 | issue = 19 | pages = 2531–4 | date = November 1998 | pmid = 9824164 | doi = 10.1038/sj.onc.1202475 | doi-access = free }}</ref>
* [[PLK1]],<ref name=pmid12815053/><ref name=pmid14647413>{{cite journal | vauthors = Lee M, Daniels MJ, Venkitaraman AR | title = Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression | journal = Oncogene | volume = 23 | issue = 4 | pages = 865–72 | date = January 2004 | pmid = 14647413 | doi = 10.1038/sj.onc.1207223 | doi-access = free }}</ref>
* [[RAD51]],<ref name=pmid14636569/><ref name=pmid11477095>{{cite journal | vauthors = Sarkisian CJ, Master SR, Huber LJ, Ha SI, Chodosh LA | title = Analysis of murine Brca2 reveals conservation of protein-protein interactions but differences in nuclear localization signals | journal = J. Biol. Chem. | volume = 276 | issue = 40 | pages = 37640–8 | date = October 2001 | pmid = 11477095 | doi = 10.1074/jbc.M106281200 | doi-access = free }}</ref><ref name=pmid12815053>{{cite journal | vauthors = Lin HR, Ting NS, Qin J, Lee WH | title = M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex | journal = J. Biol. Chem. | volume = 278 | issue = 38 | pages = 35979–87 | date = September 2003 | pmid = 12815053 | doi = 10.1074/jbc.M210659200 | doi-access = free }}</ref><ref name=pmid9126738>{{cite journal | vauthors = Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A | title = Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 | journal = Nature | volume = 386 | issue = 6627 | pages = 804–10 | date = April 1997 | pmid = 9126738 | doi = 10.1038/386804a0 | bibcode = 1997Natur.386..804S | hdl = 11858/00-001M-0000-0010-5059-F | s2cid = 4238943 | hdl-access = free }}</ref><ref name=pmid14580352>{{cite journal | vauthors = Yu DS, Sonoda E, Takeda S, Huang CL, Pellegrini L, Blundell TL, Venkitaraman AR | title = Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2 | journal = Mol. Cell | volume = 12 | issue = 4 | pages = 1029–41 | date = October 2003 | pmid = 14580352 | doi = 10.1016/S1097-2765(03)00394-0 | doi-access = free }}</ref><ref name=pmid9560268>{{cite journal | vauthors = Chen PL, Chen CF, Chen Y, Xiao J, Sharp ZD, Lee WH | title = The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment | journal = [[PNAS|Proc. Natl. Acad. Sci. U.S.A.]] | volume = 95 | issue = 9 | pages = 5287–92 | date = April 1998 | pmid = 9560268 | pmc = 20253 | doi = 10.1073/pnas.95.9.5287 | bibcode = 1998PNAS...95.5287C | doi-access = free }}</ref><ref name=pmid9405383>{{cite journal | vauthors = Wong AK, Pero R, Ormonde PA, Tavtigian SV, Bartel PL | title = RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2 | journal = J. Biol. Chem. | volume = 272 | issue = 51 | pages = 31941–4 | date = December 1997 | pmid = 9405383 | doi = 10.1074/jbc.272.51.31941 | doi-access = free }}</ref><ref name=pmid9523196>{{cite journal | vauthors = Katagiri T, Saito H, Shinohara A, Ogawa H, Kamada N, Nakamura Y, Miki Y | title = Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51 | journal = Genes Chromosomes Cancer | volume = 21 | issue = 3 | pages = 217–22 | date = March 1998 | pmid = 9523196 | doi = 10.1002/(SICI)1098-2264(199803)21:3<217::AID-GCC5>3.0.CO;2-2 | s2cid = 45954246 }}</ref><ref name=pmid12442171>{{cite journal | vauthors = Pellegrini L, Yu DS, Lo T, Anand S, Lee M, Blundell TL, Venkitaraman AR | title = Insights into DNA recombination from the structure of a RAD51-BRCA2 complex | journal = Nature | volume = 420 | issue = 6913 | pages = 287–93 | date = November 2002 | pmid = 12442171 | doi = 10.1038/nature01230 | bibcode = 2002Natur.420..287P | s2cid = 4359383 }}</ref><ref name=pmid15065660>{{cite journal | vauthors = Tarsounas M, Davies AA, West SC | title = RAD51 localization and activation following DNA damage | journal = Philos. Trans. R. Soc. Lond. B Biol. Sci. | volume = 359 | issue = 1441 | pages = 87–93 | date = January 2004 | pmid = 15065660 | pmc = 1693300 | doi = 10.1098/rstb.2003.1368 }}</ref><ref name=pmid11313963>{{cite journal | vauthors = Liu J, Yuan Y, Huan J, Shen Z | title = Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2 | journal = Oncogene | volume = 20 | issue = 3 | pages = 336–45 | date = January 2001 | pmid = 11313963 | doi = 10.1038/sj.onc.1204098 | doi-access = free }}</ref><ref name=pmid9774970>{{cite journal | vauthors = Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R | title = Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells | journal = Mol. Cell | volume = 2 | issue = 3 | pages = 317–28 | date = September 1998 | pmid = 9774970 | doi = 10.1016/S1097-2765(00)80276-2 | doi-access = free }}</ref><ref name=pmid9811893>{{cite journal | vauthors = Marmorstein LY, Ouchi T, Aaronson SA | title = The BRCA2 gene product functionally interacts with p53 and RAD51 | journal = [[PNAS|Proc. Natl. Acad. Sci. U.S.A.]] | volume = 95 | issue = 23 | pages = 13869–74 | date = November 1998 | pmid = 9811893 | pmc = 24938 | doi = 10.1073/pnas.95.23.13869 | bibcode = 1998PNAS...9513869M | doi-access = free }}</ref>
* [[Replication protein A1|RPA1]],<ref name=pmid12527904>{{cite journal | vauthors = Wong JM, Ionescu D, Ingles CJ | title = Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2 | journal = Oncogene | volume = 22 | issue = 1 | pages = 28–33 | date = January 2003 | pmid = 12527904 | doi = 10.1038/sj.onc.1206071 | doi-access = free }}</ref>
* [[SHFM1]]<ref name=pmid10373512>{{cite journal | vauthors = Marston NJ, Richards WJ, Hughes D, Bertwistle D, Marshall CJ, Ashworth A | title = Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals | journal = Mol. Cell. Biol. | volume = 19 | issue = 7 | pages = 4633–42 | date = July 1999 | pmid = 10373512 | pmc = 84261 | doi =  10.1128/MCB.19.7.4633}}</ref><ref name=pmid12228710>{{cite journal | vauthors = Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP | title = BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure | journal = [[Science (journal)|Science]] | volume = 297 | issue = 5588 | pages = 1837–48 | date = September 2002 | pmid = 12228710 | doi = 10.1126/science.297.5588.1837 | bibcode = 2002Sci...297.1837Y }}</ref> and
* [[mothers against decapentaplegic homolog 3|SMAD3]].<ref name=pmid12165866>{{cite journal | vauthors = Preobrazhenska O, Yakymovych M, Kanamoto T, Yakymovych I, Stoika R, Heldin CH, Souchelnytskyi S | title = BRCA2 and Smad3 synergize in regulation of gene transcription | journal = Oncogene | volume = 21 | issue = 36 | pages = 5660–4 | date = August 2002 | pmid = 12165866 | doi = 10.1038/sj.onc.1205732 | doi-access = free }}</ref>
{{Div col end}}

== Domain architecture ==
{{Infobox protein family
| Symbol = BRCA2
| Name = BRCA2 repeat
| image = PDB 1n0w EBI.jpg
| width =
| caption = crystal structure of a rad51-brca2 brc repeat complex
| Pfam = PF00634
| Pfam_clan =
| InterPro = IPR002093
| SMART =
| PROSITE =
| MEROPS =
| SCOP = 1n0w
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}

BRCA2 contains a number of 39 [[amino acid]] [[tandem repeat|repeats]] that are critical for binding to [[RAD51]] (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment.<ref name="pmid9811893" /><ref name="pmid9560268" /><ref name="pmid9405383" /><ref name="pmid8673099">{{cite journal | vauthors = Bork P, Blomberg N, Nilges M | title = Internal repeats in the BRCA2 protein sequence | journal = Nat. Genet. | volume = 13 | issue = 1 | pages = 22–3 | date = May 1996 | pmid = 8673099 | doi = 10.1038/ng0596-22 | s2cid = 2312211 }}</ref>

The BRCA2 helical domain adopts a [[Helix|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 [[Alpha helix|helices]] (alpha 2 to alpha 4), meanders around the surface of the core [[secondary structure|structure]]. In BRCA2, the alpha 9 and alpha 10 helices pack with the BRCA2 OB1 domain through [[Van der Waals force|van der Waals]] contacts involving [[hydrophobic]] and aromatic residues, and also through [[Side chain|side-chain]] and backbone [[hydrogen bonds]]. This domain [[molecular binding|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 (genetics)|locus]] [[deletion (genetics)|deleted]] in an inherited developmental malformation syndrome.<ref name="pmid12228710" />

The BRCA OB1 domain assumes an [[OB-fold|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 (molecular)|binding]]. The domain also [[molecular binding|binds]] the 70-amino acid [[DSS1]] (deleted in split-hand/split foot syndrome) protein.<ref name="pmid12228710"/>

The BRCA OB3 domain assumes an [[OB-fold|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 (molecular)|binding]].<ref name="pmid12228710"/>

The Tower domain adopts a [[secondary structure]] consisting of a pair of long, [[antiparallel (biochemistry)|antiparallel]] [[alpha helix|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 (molecular)|binding]] [[protein domain|domains]] of the [[bacteria]]l site-specific [[recombinases]], and of [[eukaryotic]] [[MYB (gene)|Myb]] and [[homeodomain]] [[transcription factor]]s. The Tower domain has an important role in the [[Tumor suppressor gene|tumour suppressor]] function of BRCA2, and is essential for appropriate binding of BRCA2 to DNA.<ref name="pmid12228710" /> Studies shown that conformation of this tower domain is allosterically controlled by a small protein "DSS1", which interacts with helical, OB1 and OB2 domains of BRCA2.<ref>{{cite journal | vauthors = Alagar S, Bahadur RP | title = DSS1 allosterically regulates the conformation of the tower domain of BRCA2 that has dsDNA binding specificity for homologous recombination | journal = International Journal of Biological Macromolecules | volume = 165 | issue = Pt A | pages = 918–929 | date = December 2020 | pmid = 33011260 | doi = 10.1016/j.ijbiomac.2020.09.230 | s2cid = 222165754 }}</ref>

==Patents, enforcement, litigation, and controversy==
{{Main|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;<ref name="US_5747282" />  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.<ref name=492Patent />  Myriad is the exclusive licensee of these [[Biological patent|patents]] and has enforced them in the US against clinical diagnostic labs.<ref name=SchwartzNYTimes />  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;<ref name=MyriadInvestorPage /> 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.<ref name=SchwartzNYTimes /><ref name="url BRCA1 patent legal battle">{{cite news | url =http://edition.cnn.com/2009/HEALTH/05/12/us.genes.lawsuit/index.html | title = ACLU sues over patents on breast cancer genes | publisher = CNN | access-date = 2009-05-14| archive-url= https://web.archive.org/web/20090515095043/http://edition.cnn.com/2009/HEALTH/05/12/us.genes.lawsuit/index.html | archive-date= 15 May 2009 | url-status= live}}</ref>  The patents begin to expire in 2014.

Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.<ref>{{cite web |vauthors=Conley J, Vorhous D, Cook-Deegan J | title = How Will Myriad Respond to the Next Generation of BRCA Testing?|url=http://www.genomicslawreport.com/index.php/2011/03/01/how-will-myriad-respond-to-the-next-generation-of-brca-testing/ | publisher = Robinson, Bradshaw, and Hinson | date = 2011-03-01 | access-date = 2012-12-09 }}</ref>

Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of [[genetic testing]] in general.<ref name="urlGenetics and Patenting">{{cite web | url = http://www.ornl.gov/sci/techresources/Human_Genome/elsi/patents.shtml | title = Genetics and Patenting | date = 2010-07-07 | work = Human Genome Project Information | publisher = U.S. Department of Energy Genome Programs | access-date = 2012-04-10 | archive-date = 2013-07-10 | archive-url = https://web.archive.org/web/20130710075026/http://www.ornl.gov/sci/techresources/Human_Genome/elsi/patents.shtml }}</ref>  In June 2013, in  ''Association for Molecular Pathology v. Myriad Genetics'' (No. 12-398), the [[Supreme Court of the United States|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.<ref>{{cite news| vauthors = Liptak A |title=Supreme Court Rules Human Genes May Not Be Patented|url=https://www.nytimes.com/2013/06/14/us/supreme-court-rules-human-genes-may-not-be-patented.html?_r=0|access-date=13 June 2013|newspaper=New York Times|date=13 June 2013}}</ref>  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,<ref>{{cite news|title = Landmark patent ruling over breast cancer gene BRCA1|date = February 15, 2013| vauthors = Corderoy A |url = http://www.smh.com.au/national/health/landmark-patent-ruling-over-breast-cancer-gene-brca1-20130215-2egsq.html|access-date = June 14, 2013|newspaper = [[Sydney Morning Herald]]}}</ref> but this decision is being appealed and the appeal will include consideration of the US Supreme Court ruling.<ref>{{cite news|title = Companies can't patent genes, US court rules|date = June 14, 2013| vauthors = Corderoy A |url = http://www.smh.com.au/technology/sci-tech/companies-cant-patent-genes-us-court-rules-20130614-2o836.html|access-date = June 14, 2013|newspaper = [[Sydney Morning Herald]]}}</ref>{{break}}

== References ==
{{reflist|colwidth=32em}}

== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Zou JP, Hirose Y, Siddique H, Rao VN, Reddy ES | title = Structure and expression of variant BRCA2a lacking the transactivation domain | journal = [[Oncology Reports]] | volume = 6 | issue = 2 | pages = 437–40 | year = 1999 | pmid = 10023017 | doi = 10.3892/or.6.2.437 }}
* {{cite journal | vauthors = Venkitaraman AR | title = Chromosome stability, DNA recombination and the BRCA2 tumour suppressor | journal = [[Current Opinion in Cell Biology]] | volume = 13 | issue = 3 | pages = 338–43 | year = 2001 | pmid = 11343905 | doi = 10.1016/S0955-0674(00)00217-9 }}
* {{cite journal | vauthors = Orelli BJ, Bishop DK | title = BRCA2 and homologous recombination | journal = [[Breast Cancer Research]] | volume = 3 | issue = 5 | pages = 294–8 | year = 2001 | pmid = 11597317 | pmc = 138691 | doi = 10.1186/bcr310 | doi-access = free }}
* {{cite journal | vauthors = Daniel DC | title = Highlight: BRCA1 and BRCA2 proteins in breast cancer | journal = [[Microscopy Research and Technique]] | volume = 59 | issue = 1 | pages = 68–83 | year = 2002 | pmid = 12242698 | doi = 10.1002/jemt.10178 | s2cid = 30091586 | doi-access = free }}
* {{cite journal | vauthors = Tutt A, Ashworth A | title = The relationship between the roles of BRCA genes in DNA repair and cancer predisposition | journal = [[Trends in Molecular Medicine]] | volume = 8 | issue = 12 | pages = 571–6 | year = 2003 | pmid = 12470990 | doi = 10.1016/S1471-4914(02)02434-6 }}
* {{cite journal | vauthors = Gonçalves A, Viens P, Sobol H, Maraninchi D, Bertucci F | title = [Molecular alterations in breast cancer: clinical implications and new analytical tools] | journal = [[Revue de Médecine Interne]] | volume = 26 | issue = 6 | pages = 470–8 | year = 2005 | pmid = 15936476 | doi = 10.1016/j.revmed.2004.11.012 }}
* {{cite journal | vauthors = Hay T, Clarke AR | title = DNA damage hypersensitivity in cells lacking BRCA2: a review of in vitro and in vivo data | journal = [[Biochemical Society Transactions]] | volume = 33 | issue = Pt 4 | pages = 715–7 | year = 2005 | pmid = 16042582 | doi = 10.1042/BST0330715 }}
* {{cite journal | vauthors = Domchek SM, Weber BL | title = Clinical management of BRCA1 and BRCA2 mutation carriers |journal = [[Oncogene (journal)|Oncogene]] | volume = 25 | issue = 43 | pages = 5825–31 | year = 2006 | pmid = 16998496 | doi = 10.1038/sj.onc.1209881 | doi-access = free }}
* {{cite journal | vauthors = Honrado E, Osorio A, Palacios J, Benitez J | title = Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations | journal = Oncogene | volume = 25 | issue = 43 | pages = 5837–45 | year = 2006 | pmid = 16998498 | doi = 10.1038/sj.onc.1209875 | s2cid = 20960561 | doi-access = free }}
{{refend}}

== External links ==
* {{MeshName|BRCA2+Protein|3=BRCA2 Protein}}

{{PDB Gallery|geneid=675}}
{{Tumor suppressor genes}}

{{InterPro content|IPR002093}}

{{InterPro content|IPR015252}}

{{InterPro content|IPR015187}}

{{InterPro content|IPR015205}}

{{DEFAULTSORT:Brca2}}
[[Category:Protein families]]
[[Category:Tumor suppressor genes]]
[[Category:Tumor markers]]
[[Category:Breast cancer]]
[[Category:Genes on human chromosome 13]]
[[Category:DNA repair]]
|}