Editing BRCA2 (section)

== 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.

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! 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)
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| 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>
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| 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>
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| 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>
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| 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 | pages = 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>
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| 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>
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| Icelanders || 999del5 ||<ref name="Thorlacius1996"/><ref name="Thorlacius1997"/>
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| 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>
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| 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>
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| 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>
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| Scottish || 6503delTT ||<ref name="TSNI2003"/>
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| 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>
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| 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>
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| 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>
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| 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>
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