Detection of mutations in hereditary breast and ovarian cancer-related BRCA1 and BRCA2 genes is an effective method of cancer prevention and early detection. Different ethnic and geographical regions have different BRCA1 and BRCA2 mutation spectrum and prevalence. Along with the emerging targeted therapy, demand and uptake for rapid BRCA1/2 mutations testing will increase in a near future. However, current patients selection and genetic testing strategies in most countries impose significant lag in this practice. The knowledge of the genetic structure of particular populations is important for the developing of effective screening protocol and may provide more efficient approach for the individualization of genetic testing. Elucidating of founder effect in BRCA1/2 genes can have an impact on the management of hereditary cancer families on a national and international healthcare system level, making genetic testing more affordable and cost-effective. The purpose of this review is to summarize current evidence about the BRCA1/2 founder mutations diversity in European populations.
The most significant and well characterized genetic risk factors for breast and/or ovarian cancer to date are germline mutations of the BRCA1 (MIM#113705; 17q chromosome; ) and BRCA2 (MIM#600185; 13q chromosome ) genes. In the general population, about 5–10% of all breast cancer and 10–15% of ovarian cancer cases can be attributed to these major genetic risk factors, which can explain around half of breast/ovarian cancer aggregation in some families [3, 4]. The prevalence of BRCA1/2 mutation carriers in the general population is around 0.2% (1/500) what accounts for BRCA1 mutation rate carriers of around 1/800 , however it can vary significantly among different countries or some ethnic groups due to founder effect .
The mutations in these high-penetrance genes confer a high life-time risk of breast and ovarian cancer. Women with an inherited BRCA1 mutation have a lifetime risk of 65–80% of developing breast cancer and 37–62% of developing ovarian cancer, while BRCA2 mutation carriers have a lifetime risk of 45–85% for breast cancer and 11–23% for ovarian cancer .
The identification of BRCA1 and BRCA2 mutation carriers and individualized risk assessment is an important procedure growing in clinical importance, since management protocols for mutation carriers become well established [8–10] and proven life-saving, risk-reducing preventive medical interventions exist [11–13]. Once mutation is identified in a given family, a very informative predictive (or presymptomatic) oncogenetic test can be offered virtually to all adult family members. Moreover, oncogenetic testing is becoming the powerful therapeutical predictive tool, as new targeted therapeutic opportunities, such as poly(ADP-ribose) (PARP) inhibitors [14, 15], emerge and chemosensitivity to platinum based therapy is constantly reported [16, 17].
Currently, in most countries clinical BRCA1/2 testing is offered after genetic counseling by clinical cancer geneticist (oncogeneticist) when mutation finding probability exceeds 10%, or even 20% (as in the UK) . Various selection criteria, based on family history, age at onset and tumors clinicopathological features, as well as computational risk prediction models (Claus, BRCAPRO, BOADICEA, IBIS, Myriad and Manchester scoring system [19, 20]) are used. Unfortunately, these models often underestimate the probability of finding a mutation, are validated only in some countries, are not particularly helpful for daily use and no consensus exist regarding their common use [9, 21]. Moreover, familial history is also absent or unknown in at least half of all mutation possitive families  and mutation detection methods varies between most centers.
It is now evident, that in a near future the uptake and demand for rapid BRCA1/2 mutations testing will increase and more flexible genetic counseling strategies will be needed. As new targeted therapies become available, more individuals will request testing to get access to specific treatments (i.e., PARP inhibitors), regardless of their a priori low risk and clinicians will force laboratories towards rapid testing results. This tendency is already seen in the centers enroling patients for PARP inhibitors clinical trials (van Osterweik, personal communication) as well as during peridiagnostic (presurgical) testing for a newly diagnozed breast cancer patients .
However, a full BRCA1 and BRCA2 gene screening still remains labor and time consuming challenge due to large genes size, diverse mutations or variants of unknown significance (VUS) and complexity of large genomic rearangements (LGRs), requiring special technical approach. This procedure still remains too complex and expensive to cover a broader target (e.g. all breast or ovarian cancer patients and their first degree relatives) and cannot be routinely applied in less privileged countries.
Fortunately, recent advances in high-throughput mutation detection and screening techniques, such as high resolution melting (HRM) analysis  and conformation-sensitive capillary electrophoresis (CSCE)  are especially promising rapid, sensitive, cost-efficient and ammenable for automation screening approaches for the large genes, whereas decreased cost in genotyping methods offers affordable targeted testing option for predefined set of mutations.
Massively parallel next-generation sequencing platforms  provide another technological breakthrough, however they are still at a prohibited cost and complex data overload for routine use.
On the other hand, variation in the distribution of BRCA1 and BRCA2 mutations is well recognized worldwide  and several recent reviews already summarized the evidence, that in certain countries and ethnic communities the BRCA1/2 mutation spectrum is limited to a few founder mutations [3, 4, 6, 28]. Founder effects are most prominent in geographically, culturally or religiously isolated populations that undergo rapid expansion from a limited number of ancestors, when, as a consequence of low genetic diversity, some alleles become more frequent.
The purpose of this review is to summarize current evidence about the BRCA1/2 founder mutations diversity in European populations. For the current manuscript only the unequivocally deleterious mutations were considered, excluding as yet the unclassified variants that could not be clearly related with pathogenicity. For the consistency, the unequivocal term “founder” is used for those mutations where haplotype studies revealed shared polymorphic markers consistent with common ancestor, or when unrelated mutation carriers were repeatedly identified (at least 3 times). Some mutations previously described as founder mutations in one country, subsequently are found at a higher proportion in other countries/regions as true founders. These mutations in adjacent countries will likely reflect the gradient transition from the “epicenter” over the time due to historical co-existence of different populations in the same region. Mutations that do not segregate with the same alleles are referred as “recurrent”. They presumably occurred several times at unstable ‘mutational hot spots’ parts of the gene. The mutation nomenclature will be generally presented according to Human Genome Variation Society (HGVS) recommendations (http://www.hgvs.org/rec.html); only at the first mutation mention the older BIC database (http://research.nhgri.nih.gov/bic/) nomenclature will be used between the parentheses, where possible. BRCA1 is numbered by GeneBank U14680 reference sequence; BRCA2 is numbered by GeneBank U43746 reference sequence.
For the mutations distribution in other geographic regions or more detailed prevalence, penetrance and contribution to unselected for family history cancer cases, readers are referred to other review sources [3, 4, 6, 27–30].
Founder BRCA1 and BRCA2 mutations in European populations
The BRCA1/2 founder effect in Ashkenazi Jews population is very well described. About 10 millions Ashkenazi people living worldwide are descendants of ancestors from Eastern and Central Europe, such as Poland, Lithuania, Belarus, Germany, Hungary, Ukraine and Russia. The most well characterized three founder mutations are two in BRCA1 gene c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT) [31–33]. Screening for these three founder mutations alone is now part of routine clinical practice for Ashkenazi Jewish individuals.
These 3 mutations (BRCA1 c.68_69delAG, c.5266dupC and BRCA2 c.5946delT) account for 98–99% of identified mutations and are carried by about 2.6% (1/40) of the Ashkenazi Jewish population (1%, 0.13% and 1.52% respectively) [34–36]. There are differences between particular mutations and breast/ovarian cancer risk . The average risk of breast cancer by the age of 70 years is similar for carriers of the BRCA1 c.68_69delAG and c.5266dupC mutations (64% and 67% respectively), however is much lower for the c.5946delT mutation (43%). The corresponding values for ovarian cancer lifetime risk is respectively of 14%, 33% and 20% in carriers, respectively [6, 37, 38].
It is worth noting that BRCA1 c.68_69delAG and c.5266dupC are not found exclusively in Ashkenazi patients. The c.68_69delAG mutation has been found in patients of Spanish ancestry (i.e. Hispanic) as well as other non-Ashkenazi ethnic groups, sometimes with frequencies similar to those in Ashkenazi populations , suggesting a common ancient ancestor or two independent mutational events .
The c.5266dupC mutation in BRCA1 exon 20 is the second most frequently reported mutation in the BIC database, being very prevalent in Central and Eastern Europe. This single mutation is found in a various frequency in high risk breast and/or ovarian cancer families from Poland (34%) , Russia (14%) , Hungary (14%) , Slovenia (13%) , Ashkenazi Jews (10%) , Greece (8%) , Germany (4%) , Italy (3%) . It is virtually absent in Spain and Portugal and is found at low frequency in the Netherlands, Belgium and Scandinavian countries . In Russia, Belarus, Poland, Latvia, Czech Republic, Greece and Lithuania this mutation accounts for respectively 94% , 73% , 60% , 55% , 37–52% [51, 52], 46% , 34% [53, 54] of all BRCA1 mutations.
Haplotype analysis points to the Baltic origin of this mutation approximately 38 generations ago during the medieval period , with a gradual decrease thereafter from East to the West and nearly worldwide spread. A common ancestor for c.5266dupC mutation families reported from Europe, Brazil and North America is evident [46, 56, 57].
In Austria the ratio of BRCA1 mutations to BRCA2 mutations is 2:1 (Rappaport, personal communication). There were initial reports for several apparently founder BRCA1 mutations in Austria [58, 59], although they (c.181T>G (BIC: 300T>G/C61G), c.5266dupC, c.1687C>T (BIC: 1806C>T)) represent common mutations prevalent in other European countries. In Austria these alterations represent 15%, 10% and 6% of the BRCA1 mutation families, respectively (Rappaport, personal communication). Of note, c.1687C>T is also frequent in Slovenia  and Sweden (BIC database). Haplotype analysis revealed a common ancestor for the Austrian and Swedish families, which may indicate Austrian origin of this mutation , although its even more common in Slovenia (26% of the BRCA1 mutation families) . Another common mutation is BRCA1 c.3016_3019del4 (BIC: 3135del4) (8% of the BRCA1 mutation families), which was also found in Italy . One BRCA1 mutation c.2676_2679del4 (BIC: 2795del4) was reported at least in three unrelated families in Austria only, what may represent founder effect [58, 59], however this mutation is uncommon. The most prevalent BRCA2 mutations are c.8363G>A (BIC: 8591G>A/W2788X), c.8754+1G>A (BIC: IVS21-1G>A) and c.3860delA (BIC: 4088delA), representing 9%, 7% and 6% of the BRCA2 mutation families respectively (Rappaport, personal communication).
In Slovenia five highly recurrent specific mutations were identified: four in the BRCA1 gene (c.1687C>T, c.181T>G, c.5266dupC, c.181T> (BIC: 300T>A)) and one in the BRCA2 gene (c.7806-2A>G (BIC: IVS16-2A>G) [43, 61, 62]. Respectively, they accounted for 26%, 18%, 13% and 11% of BRCA1 mutations and 56% of BRCA2 mutations. The c.7806-2A>G in the BRCA2 gene appears to be an unique founder mutation in the Slovenian population, found in 26% (10/38) of all BRCA1/2 mutations harboring families. These 5 mutations account for 67% of the BRCA1/2 positive families .
Four distinct BRCA1 founder mutations (c.3228_3229delAG (BIC: 3347delAG), c.3285delA (BIC: 3404delA), c.1380dupA (BIC: 1499insA), c.5062_5064del3 (BIC: 5181delGTT) accounted for a large fraction (73%) of BRCA1-attributable hereditary breast/ovarian cancer in families originating from Tuscany (Central Italy) area [47, 66].
The BRCA1 c.1380dupA mutation was reported in at least 14 families from Tuscany and originated here about 30 generations ago (∼750 years) .
In Sardinia, contribution of BRCA1/2 mutations to breast cancer predisposition has been reported for populations from the Northern part of the island , where founder BRCA2 c.8537_8538delAG (BIC: 8765delAG) mutation comprises 28% for BRCA1/2 positive families [68, 69]. The ratio of BRCA2 mutations to BRCA1 mutations is approximately 2:1, although BRCA1 being more prevalent in South-West area . Conversely, previously regarded as another founder mutation, BRCA2 3950_3952delTAGinsAT was found instead running in families belonging to a single extended pedigree .
The BRCA1 c.4964_4982del19 (BIC: 5083del19) is a founder mutation from the southern region of Calabria and accounted for 23% of all BRCA1 mutations [60, 63]. It was also recurrently found at least four times in Sicilia [70, 71]. Another BRCA1 c.4724delC (BIC: 4843delC) mutation could be a possible Sicilian founder mutation, although present evidence is scarce [71–73].
Using a number of independent approaches, Malacrida et al.  showed that previously reported BRCA1 c.5062_5064delGTT (BIC: 5181_5183delGTT/1688Val) variant of unknown significance (VUS) actually is a deleterious mutation with high frequency in North-East Italy . The founder c.5062_5064delGTT mutation accounts for 15% (9/61) of families with small BRCA1 mutations.
In France geographical clustering in North-Eastern part is evident for two recurrent BRCA1 mutations, suggesting a founder effect. The c.3481_3491del11 (BIC: 3600del11) in exon 11 accounts for 37% and the nonsense mutation c.5128G>T (BIC: 5247G>T/Gly1710X) in exon 18 for 15% of all BRCA1/2 mutations in that region (overall 52%) [4, 75].
The haplotype analysis of the families carrying the mutation c.3481_3491del11, all originating from Alsace–Lorraine, revealed the presence of a common allele, indicating a founder effect . Although this mutation is found in many different geographical areas, it is more common in France. The BRCA1 mutation c.5128G>T would appear to be specific to the France, but the analysis of its haplotype is less conclusive and needs further confirmation .
Well-described founder mutations are identified in French-Canadians population in Quebec, which originated from France during 17–18th century settlement period. In this region 4 BRCA1 gene mutations (c.4327C>T (BIC: 4446C>T/Arg1443X), c.3756_3759del4 (BIC: 3875delGTCT), c.962G>A (BIC: 1081G>A), c.2834_2836delinsC (BIC: 2953delGTA/insC) and 3 BRCA2 mutations (c.3170_3174del5 (BIC: 3398del5), c.5857G>T (BIC: 6085G>T), c.8537_8538delAG (BIC: 8765delAG)) are now routinely included in early onset breast/ovarian cancer screening assays and represent up to 84% of the total BRCA1/2 mutations in the French-Canadian population in Quebec . Among these, the most common founder mutations are BRCA1 c.4327C>T and BRCA2 c.8537_8538delAG and c.3170_3174del5, which are found in 1.7% of women affected by breast cancer diagnosed before age 41 and in 1.3% of women with ovarian cancer .
In Spain, five mutations in BRCA1 and other five in BRCA2 genes account for approximately half of the mutations detected in Spanish families. Specific mutations differ significantly in their frequencies and geographic distribution.
A compilation of BRCA test results from different laboratories shows that five mutations in the BRCA1 gene (c.68_69delAG, c.211A>G (BIC: 330A>G), c.5117G>A (BIC: 5236G>A), c.5123C>A (BIC: 5242C>A), c.470_471delCT (BIC: 589_590delCT) account for 46.6% of BRCA1 mutations and four mutations in BRCA2 (c.2808_2811del4 (BIC: 3036_3039del4), c.6629_6630delAA (BIC: c.6857delAA), c.9026_9030del5 (BIC: 9254-9258del5), c.9310_9311delAA (BIC: 9538delAA)) account for 56.6% of the BRCA2 mutations .
Diez et al.,  have reviewed the frequency of BRCA1 and BRCA2 recurrent mutations reported in seven geographic areas of Spain.
The founder mutation BRCA1 c.211A>G, that leads to aberrant splicing of the transcript, originates from North Western Spain (Galicia) and accounts up to 50% of all mutations in this region . It was also found in French and British families of Spanish origin .
The BRCA1 c.68_69delAG and BRCA2 c.9026_9030del5 mutations accounted for the 30.4% (7/23) of the BRCA1 mutations and for the 18.5% (5/27) of the BRCA2 positive families respectively and were specific only to the Mediterranean areas. Indeed, haplotype studies indicated a common origin of c.68_69delAG mutation in Spanish (Sephardic Jewish) and Ashkenazi Jewish populations . Some data indicate an unique origin of reported BRCA2 exon 23 mutation BRCA2 c.9026_9030del5 in Catalan families (North-East Spain) . Likewise, the BRCA2 c.2808_2811del4 mutation was predominant only in the Castilla-Leon region (Central Spain), but it also has been described worldwide in many populations and is the second recurrent pathological mutation in the BIC database ranking with a presumable multiple different origins [85, 86].
Splicing mutation c.5153-1G>A (BIC: 5272-1G>A) of BRCA1 and frameshift mutation c.5146_5149del4 (BIC: 5374delTATG) of BRCA2 are also prevalent founder mutations in the Central Spain region, accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively [80, 85, 87]. Such knowledge of the spectrum of mutations and their geographical distribution can allow a more effective detection strategy in countries with large Spanish population.
Conversely, in the Basque population, only 1.2% (1/81) of early onset breast cancer women unselected for family history had pathological mutations; no founder mutation was identified .
An Alu sequence insertion in BRCA2 exon 3 (c.156_157insAlu (BIC: 384insAlu)) is a founder mutation of Portuguese origin and accounts for more than one-fourth of deleterious BRCA1/2 mutations in breast/ovarian cancer families in Northern/Central Portugal. This mutation creates BRCA2 exon 3 skipping and is the most frequent large BRCA2 rearrangement described to date [89, 90].
Claes et al.  in a 49 BRCA1/2 positive families found six major recurrent founder mutations (three BRCA1 c.212+3A> (BIC: IVS5+3A>G), c.2359dupG (BIC: 2478insG), c.3661G>T (BIC: 3780G>T) and three BRCA2 c.516+1G>A (BIC: IVS6+1G>A), c.6275_6276delTT (BIC: 6503_6504delTT), c.8904delC (BIC: 9132delC) alterations), which accounted for nearly 60% of all mutations identified. BRCA1 c.212+3A>G was previously reported as Belgian founder mutation [92, 93], later also found in a few German, Dutch and French families . BRCA1 c.2359dupG and BRCA2 c.516+1G>A have not yet been reported in other populations.
The Netherlands (Holland)
Several founder mutations in BRCA1/2 have been identified in Holland , where significant regional and cultural differences exist. The BRCA1 c.2685_2686delAA (BIC: 2804delAA) founder mutation probably originated approximately 32 generations (∼200 years) ago, was also reported few times in Belgium and accounted for 24% of all BRCA1/2 mutations . BRCA1 c.2193del5 (BIC: 2312del5), and c.1292dupT (BIC: 1411insT) mutations were also commonly found [92, 94].
In the south-west of Holland two founder mutations: 3.8-kb deletion of BRCA1 exon 13, also known as c.4186-1643_4357+2020del3835 (BIC: del exon 13del3835/IVS12-1643del3835), and BRCA2 c.5351dupA (BIC: 5579insA) were found in families from two different geographical areas, and were prevalent respectively in Catholic (West Braband clustering) and Protestant (South Beveland clustering) families, reflecting religious endogamy . Together with another Dutch BRCA2 founder mutation c.6275_6276delTT (BIC: 6503delTT), c.5351dupA accounts for 62% of hereditary breast/ovarian families [94, 95].
Slightly outdated (as of year 2002) list of published and unpublished BRCA1/2 mutations in Netherlands and Belgium can be found at http://www.humgen.nl/lab-devilee/Lab/b1nlmuts.htm.
Large genomic rearrangements (LGRs) in BRCA1 gene are surprisingly common in Dutch population and more than 30% of the BRCA1 related cases of hereditary breast cancer are due to copy number changes of one or more exon in this gene. The majority of these (25%) are due to two frequently occurring founder mutations: already described 3.8-kb deletion of exon 13 or 510-bp deletion of exon 22 , which can be easily detected by multiplex-ligation dependent probe amplification (MLPA) method.
The BRCA1 deletion of exon 17 accounts for 8% of all the BRCA1 mutations and is the most frequent rearrangement in Germany, found in 3% of high-risk families and in 6% of families without point mutations . Altogether, recurrent aberrations such as deletion of exon 17, duplication of exon 13 and deletion of exon 22, accounts for more than 50% of all BRCA1 large genomic rearrangements in Germany .
There was a large number of recurrent mutations with a common haplotype identified in breast/ovarian cancer patients . Eighteen BRCA1 mutations, including the most common c.5266dupC, c.181T>G, c.4065_4068del4 (BIC: 4184del4) and c.2338C>T (BIC: 2457C>T), were found at least 3 times and comprised 66% of all BRCA1 mutations. The 2 most common BRCA1 c.5266dupC and c.181T>G mutations, also prevalent in other populations, accounted for 38% of BRCA1 mutations [4, 99]. Seven distinct mutations accounted for 28% of BRCA2 mutations, and most frequent c.1813dupA (BIC: 2041insA), c.4478del4 (BIC: 4706del4) and c.9098dupA (BIC: 9326insA) were associated with common alleles, suggesting a possible founder effect .
Five mutations (BRCA1: c.181T>G, c.5266dupC, c.3700_3704del5 (BIC: 3819del5), and BRCA2: c.7913_7917del5 (BIC: 8141del5) and c.8537_8538del2 (BIC: 8765delAG)) represented 52% of all mutations detected in one study population . There is evident strong Slavic founder effect, particularly for two BRCA1 mutations (c.181T>G and c.5266dupC) also regarded as founder mutations in Poland and some other Slavic countries . The single BRCA1 c.5266dupC mutation was detected in 51.4% of BRCA1 mutation positive women in one study from Prague area . The BRCA1 c.3700_3704del5 mutation is also frequent mutation in Germany . Three BRCA1 Czech founder mutations (c.181T>G, c.3700_3704del5, and c.5266dupC) account for approximately 9%, 13% and 44% of the BRCA1 mutations identified, respectively [51, 52].
BRCA1 mutations appears to be about 2 times more frequent than BRCA2 mutations in the Czech population .
A Czech founder effect is evident for two BRCA2 mutations (c.7913_7917del5 and c.8537_8538del2), that are more frequent in Moravian (Eastern) rather than in Bohemian (Western) region . These BRCA2 mutations accounted for 15.6% and 16.7% of the BRCA2 mutations identified in one study, respectively .
LGRs in BRCA1 gene are relatively common in Czech population and account for 12.3% of all pathogenic BRCA1 mutations. The deletions of exons 1–17 and 5–14, identified each in four families, represented Czech founder mutations . No LGRs in BRCA2 gene were described so far.
The ratio of BRCA1 mutations to BRCA2 is approximately 9:2 and the most common BRCA1/2 mutations in Slovak population are three common to the Ashkenazi mutations (Zajac, personal communication). However, as yet there are no convincing data about true BRCA1/2 mutational spectrum in this population.
In Hungarian patients from high-risk breast/ovarian cancer families, common BRCA1 founder mutations c.5266dupC, c.181T>G and c.68_69delAG accounted for 80% of all BRCA1 mutations and c.9098dupA (BIC: 9326insA) with c.5946delT accounted for 50% of all BRCA2 mutations [42, 103]. The BRCA1 c.181T>G is the most frequent of founder mutations, representing 48% . Breast cancer patients were more likely to carry the c.5266dupC mutation whereas ovarian patients were more likely to carry either the c.68_69delAG or the c.181T>G mutation . Among unselected Hungarian male breast cancer patients, one third carried BRCA2 mutations, including c.9098dupA .
In the Greek population four BRCA1 mutations (c.5526dupC, c.5212G>A (BIC: 5331G>A/G1738R), c.5251C>T (BIC: 5370C>T/R1751X), c.5467G>A (BIC: 5586G>A), account for 54% of all mutations detected in BRCA1/2 genes and for 73% of the BRCA1 mutations positive families, whereas the rest are unique or low-frequency mutations, reflecting the population’s genetic heterogeneity.
Previously described as unclassified BRCA1 missense variant G1738R was proved to be pathogenic founder mutation in Greece and accounts for about 12% of all carriers with deleterious mutations in BRCA1/2 genes .
In Cypriot breast cancer women proportion of BRCA2 to BRCA1 gene mutations is approximately 2:1 . The BRCA2 c.8755delG (BIC: 8984delG) mutation was reported in three unrelated families and could represent Cypriot founder mutation [107, 108].
BRCA1 and BRCA2 small scale mutations in Denmark are a mixture of Scandinavian founder mutations and other European mutations, including BRCA1 c.5266dupC. The most common BRCA1 mutations were c.2475delC (BIC: 2594delC), c.3319G>T (BIC: 3438G>T), c.5266dupC and c.3710delT (BIC: 3829delT), which accounted 16%, 9%, 8% and 5% of BRCA1 positive families, respectively [109–111]. The c.2475delC BRCA1 mutation was also reported in Sweden, Norway and Western Europe (BIC database) and the c.3319G>T BRCA1 mutation was also reported in Norway (http://www.legeforeningen.no/id/153250.0).
The most common BRCA2 mutations were c.6373delA (BIC: 6601delA), c.1310_1013del4 (BIC: 1538del4), c.6486_6489del4 (BIC: 6714del4) and c.3847_3848delGT (BIC: 4075delGT), found in 11%, 10%, 9% and 5% of BRCA2 positive families, respectively . Two of the recurrent BRCA2 mutations (c.1310_1313del4 and c.6486_6489del4) have also been observed in many other populations, whereas the c.6373delA BRCA2 mutation is less frequent. There was a slight tendency towards a higher frequency of BRCA2 families in West Denmark (56%) compared to East Denmark (44%). Altogether 7 common BRCA1/2 mutations (excluding c.5266dupC ) accounts for around 35% of carriers .
LGRs in BRCA1 and BRCA2 are common in East Denmark and account for 9.2% (15/163) of the disease causing mutations. BRCA1 exons 3–16 deletion represents Danish founder mutation, comprising 40% (6/15) of all BRCA1/2 families with LGRs .
Recently a pathogenic founder BRCA1 mutation c.234T>G (BIC: 2466T>G/Cys39Gly) was desribed in Greenland (Inuit population), an autonomous country within the Kingdom of Denmark, with a high carrier frequency (1.6%) in this population [113, 114]. Therefore all women of Greenlandic origin are recommended to be counseled and screened for this mutation .
In Sweden, many different mutations in the BRCA1 and BRCA2 genes have been detected. The most recurrent BRCA1/2 mutation in Sweden is the single BRCA1 mutation c.3171_3175dup (BIC: 3171ins5), which originate from a limited geographic area along the west coast of Sweden . Mutation carriers have a conserved haplotype of 3,7 cM which is thought to have originated about 50 generations ago. In the western part of Sweden this mutation accounts for 65–77% of identified mutations in these two genes [116, 117]. Other common BRCA1 mutations in Sweden, c.2475delC and c.1082_1092del11 (BIC: 1201del11), have been detected primarily in families from southern Sweden [118–120], Denmark and Norway (BIC database). Another BRCA1 mutation, c.1687C>T, occurs primarily in southern Sweden as well as other European countries (BIC database). Yet another BRCA1 mutation c.3626delT (BIC: 3745delT) apparently originates in northern Sweden and Finland .
The 6-kb duplication of BRCA1 exon 13, aslo known as ins6kbEx13 (HGVS: c.4186-1787_4357+4122dup; BIC: 4305ins6000(dup_ex13) mutation, is quite common in Sweden and is apparently specific to English-speaking and related countries .
In the Western Sweden, six mutations, including the most common BRCA1 c.3171_3175dup, four other common Scandinavian BCRA1 mutations (c.1082_1092del11, c.2475delC, c.1687C>T, c.1016dupA (BIC: 1135insA)) and one BRCA2 mutation (c.4258delG) accounted for approximately 75% of all BRCA1/2 mutations . The founder mutation, BRCA1 c.3171_3175dup, may explains more than 80% of excess number of ovarian cancer after breast cancer in this region [115, 125].
Four Norwegian founder mutations in BRCA1 gene (c.1556delA (BIC: 1675delA), c.3228delAG (BIC: 3347delAG), c.697delGT (BIC: 816delGT) and c.1016dupA make up 68% of the BRCA1 mutation carriers [126, 127], and these have their own specific geographic distribution. The first three originate from the south-western region of the country, while the fourth is from the south-east .
These four founder mutations together with other six most frequent BRCA1/2 mutations (BRCA1 c.3178G>T (BIC: 3297G>T), c.4745delA (BIC: 4864delA), c.2351del7 (BIC: 2470del7), c.3084del11 (BIC: 3203del11) and BRCA2 c.2808del4 (BIC: 3036del4), c.3847delGT (BIC: 4075delGT)), account for about 60% BRCA1/2 carriers in Norway . BRCA1 c.1A>C (BIC: 120A>C) and c.5075-2A>C (BIC: IVS17-2A>C) mutations are also locally frequent. The large deletion of BRCA1 exons 1–13 is frequently found as well as exon 13 duplication (ins6kb13Ex) (http://www.inherited-cancer.com).
The BRCA1 c.1016dupA mutation has also been reported in other countries (Italy, Germany, French-Canada), however allelotyping results indicated an independent origin of this mutation. That would justify the inclusion of this mutation into targeted BRCA1 mutation screening panels in any population, irrespective of ethnic origin .
In the Finnish population, at least 13 recurrent BRCA1/2 mutations with a founder effect have been identified (6 in BRCA1 and 7 in BRCA2 gene), and these represent majority (around 84%) of all BRCA1/2 mutations detected [130–138]. The most common BRCA1 mutations are c.4097-2A>G (BIC: 4216-2A>G), c.3485delA (BIC: 3604delA), c.3626delT (BIC: 3745delT), c.4327C>T (BIC: 4446C>T), c.2684del2 (BIC: 2803delAA) and c.5251C>T (BIC: 5370C>T). The c.5266dupC is also found relatively frequently.
The most recurrent mutation in BRCA2 is the Icelandic founder mutation c.771_775del5 (BIC: 999del5), three other (c.7480C>T (BIC: 7708C>T), c.8327T>G (BIC: 8555T>G), c.9118-2A>G (BIC: 9346-2A>G) and following (c. 6384del2 (BIC: 6503delTT), c.3853dupA (BIC: 4081insA) and c.5569G>T (BIC: 5797G>T)). Some mutations are unique to the Finns, such as c.4096+3A>G (BIC: IVS11+3A>G) in BRCA1 and c.9117+1G>A (BIC: 9345+1G>A), c.7480C>T, c.8327T>G in BRCA2 genes.
The mutation spectrum in Eastern part slightly differs from those observed in the Northern and Southern parts of the country .
In Iceland, the most common single founder mutation is c.771_775del5 in the BRCA2 gene [144, 145], which accounts for virtually all breast/ovarian cancer families and simplifies genetic testing. It occurs in 0.4% (1/250) of the population, 8.5% of consecutive unselected breast cancer cases, 7.9% of ovarian cancer cases and 40% of male breast cancer cases [6, 146].
The BRCA1 c.5074G>A (BIC: 5193G>A) is another founder mutation recently identified in Icelandic population, however it is extremely rare and contributes only to 1% of breast/ovarian cancer cases .
The profound founder effect in Iceland can be traced to comparatively small number of women, mostly originating from Scandinavia and the British Isles .
There is some evidence about specific recurrent mutations confined to particular geographic regions in the UK.
In one study from Scotland and Northern Ireland 10 specific recurring mutations (five in each gene) accounted for almost half of the total mutations detected, and almost one-quarter were accounted by just two founder mutations (BRCA1 c.2681_2682delAA (BIC: 2800delAA) and BRCA2 c.6275_6276delTT (BIC: 6503delTT) . The BRCA1 c.2681_2682delAA, probably originated from the West-Central Scotland or Ireland . BRCA2 c.6275_6276delTT has been found elsewhere in the UK as well as in Dutch, Swedish, Danish and Belgian families (BIC database).
In the North-west of England two reccurent mutations (BRCA1 c.4065_4068del4 and BRCA2 c.1929delG (BIC: 2157delG) accounted for 16% of identified BRCA1 mutations in breast/ovarian cancer families and for 20% of BRCA2 positive male breast cancer families, respectively, what is around 1 in 8 of every mutation identified in each gene .
A duplication of a 6-kb fragment including BRCA1 exon 13 (ins6kbEx13), which creates a frameshift in the coding sequence, is considered to be a common founder mutation originating from Northern Britain  and comprise for 9% of BRCA1 mutations in UK [4, 152]. It is distributed mainly in English-speaking countries or in countries with historical links with Britain.
A single BRCA1 c.427G>T (BIC: 546G>T/E143X) mutation accounts for about 22% of all hereditary breast cancer patients from relatively homogenous Irish population and presumably is due to the founder effect .
There is strong founder effect in Polish population for BRCA1 gene mutations. In Poland 3 most common mutations (c.5266dupC, c.181T>G and c.4035delA (BIC: 4154delA) accounted for 91% (111/122) BRCA1 mutations detected and for 86% of all detected mutations in BRCA1/2 genes [40, 100]. The BRCA1 c.5266dupC, c.181T>G and c.4035delA accounted for about 56%, 25% and 10% of all BRCA1 mutations, respectively. Mutations in BRCA2 gene comprises for about 5.4% of all BRCA1/2 mutations identified . One of three BRCA1 founder mutations was identified in 13.5% (49/364) consecutive ovarian cancer cases and in 32.8% (58/177) women with familial ovarian cancer in Western Poland, therefore its reasonable to recommend genetic testing to all invasive ovarian cancer cases regardless the age .
Data from other groups indicate, that mutational BRCA1/2 spectrum in Poland is more dispersed and different in various subregions [155, 156]. In North-Eastern Poland two common mutations (c.5266dupC and c.181T>G) accounted for more than half (up to 70%) of all BRCA-mutated families and no c.4035delA was identified , what is in accordance with other studies . By adding two other recurring BRCA1 mutations (c.68_69delAG and c.3700_3704del5), the vast majority (87%) of mutation-positive families will be encompassed. At least 2 novel BRCA1 LGRs were found in Poland and they are not so uncommon .
In fact, observed BRCA1 founder mutations are by no means unique for Poland but rather of global or European distribution  and its necessary to extend analysis, including LGR, among patients negative for BRCA1/2 founder mutations.
In Latvia two BRCA1 mutations (c.5266dupC and c.4035delA) made up more than 80% of all mutations BRCA1 identified [50, 158]. The 4154delA mutation is the second most abundant BRCA1 gene mutation after the c.5266dupC in Latvia  and is especially common for patients of Baltic (Latvian and Lithuanian) origin. It was also reported several times from Russia, Poland, has been predominantly detected in individuals of Eastern European and also is the most characteristic BRCA1 mutation in Lithuania [53, 54]. A common shared haplotype, with probable Lithuanian origin, was reported in these mutation carriers . The BRCA1 c.181T>G is the third recurrent mutation in Latvia, but is not very commonly found. There are no data present about BRCA2 mutation profile in Latvia.
In Lithuania BRCA1 gene mutations are influenced by significant founder effect, which is similar to that reported from Latvian (Baltic) population . BRCA1 c.4035delA and c.5266dupC attributes to 86% (53% and 33% respectively) of detected BRCA1 mutations [53, 54, 160]. Two other mutations, BRCA1 c.181T>G and recently proved to be pathogenious c.5258G>C (BIC: 5377G>C/R1753T) were also found in more than one family; together with two founder mutations they comprise around 90% of BRCA1 gene mutations and around 85% of all BRCA1/2 mutations identified (Janavičius, unpublished data). Rapid screening of three BRCA1 amplicons by HRM analysis now is the innitial procedure for breast/ovarian cancer patients in our hospital.
The most frequently observed is BRCA1 c.4035delA mutation, which is more frequent in families of Baltic (Lithuanian) origin rather than Slavic [53, 54, 161], and was detected in 16.3% (7/43) of unrelated ovarian cancer patients unselected for family history in one study . Among BRCA1 positive patients in a single population, this particular mutation has the highest proportion identified to date (53%), where in neighbouring countries (Latvia, Poland, Belarus and Russia) it accounts for around 40% [Tihomirova, personal communication], 10% , 9%  and 9%  respectively of all BRCA1 mutations. This distribution is in agreement with geographic area of ancient Baltic people. Currently haplotype studies have been innitiated to confirm further the occurence and timing of this mutation in Lithuania.
Newly published data from Estonia about BRCA1/2 mutations structure showed significant involvement of BRCA1 c.5266dupC and to a lesser extent BRCA1 c.4035delA , what could be also expected projecting data from adjacent countries.
Only one small study in West Belarus for targeted BRCA1 mutations identified similar spectrum of 3 common mutations as in Poland, and c.5266dupC accounted here for 73% of all BRCA1 mutations .
In Russia the most common BRCA1 gene mutation in c.5266dupC, comprising around 90% of all BRCA1 mutations [41, 163–167]. Other less common mutations found in Western Russia are c.4035delA, c.181T>G, and c.68_69delAG. In Siberian region of Russia there is seen preponderance of individual BRCA2 gene mutations .
In some countries, such as Romania, Bulgaria, Ukraine, Malta, Albania and most previous Yugoslavian countries (Serbia, Bosnia and Herzegovina, Macedonia and Montenegro) it seems no surveys on BRCA1 and BRCA2 mutations have been yet conducted and no data are available. From Croatia no conclusive data about founder BRCA1/2 mutations pattern is available, since only some individual mutations and harmless variants were reported in one study .
The distribution of mutations in a European populations is characterized by the genetic homogeneity or heterogeneity of particular populations (Table 1). A stepwise mutation screening protocol, based on initial screening for the common mutations, is possible in populations with a high proportion of founder mutations, allowing for a more rapid, less expensive and hence, more affordable first-line genetic testing strategy. However, subsequent full BRCA1/2 testing is mandatory in most populations, probably with the exception for Ashkenazi and Icelandic individuals, where effect of few founder mutations is nearly absolute. The contribution of LGRs should be also acknowledged for most populations and specific techniques must be considered to achieve full coverage of BRCA1/2 genes. It is possible that common founder mutations remain to be identified in some populations.
Knowledge about mutation distibution diversity is important not only for the consideration of country specific cost-efficient strategy for mutation screening, but also for the breast-ovarian cancer control and prevention through more liberal, yet rational, genetic testing and counseling in a globalized landscape of postmodern Europe. Common genetic variation (e.g. single nucleotide polymorphisms (SNPs)) might also influence disease risks in BRCA1/2 carriers and this subject is being addressed on a larger scale by the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) which aims to identify genetic modifiers of breast and ovarian cancer risk in BRCA1 and BRCA2 carriers . This information might be useful for more precise risk estimation in the near future.
Personalized treatment era, based on comprehensive and rapid BRCA1/2 genetic test result is nearly here. However, taken the profoud and broad impact of possitive genetic testing result for patients and their relatives, the importance of pre- and post-test oncogenetic counseling still remain essential.
Miki Y et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.
Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–92.
Fackenthal JD, Olopade OI. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer. 2007;7:937–48.
Ramus SJ, Gayther SA. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol. 2009;3:138–50.
Mann GJ et al. Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res. 2006;8:R12.
Ferla R et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18 Suppl 6:vi93–8.
Balmana J, Diez O, Castiglione M. BRCA in breast cancer: ESMO clinical recommendations. Ann Oncol. 2009;20 Suppl 4:19–20.
Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357:154–62.
De Greve J, Sermijn E, De Brakeleer S, Ren Z, Teugels E. Hereditary breast cancer: from bench to bedside. Curr Opin Oncol. 2008;20:605–13.
Granader EJ, Dwamena B, Carlos RC. MRI and mammography surveillance of women at increased risk for breast cancer: recommendations using an evidence-based approach. Acad Radiol. 2008;15:1590–5.
Kauff ND et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26:1331–7.
Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101:80–7.
Evans DG et al. Risk reducing mastectomy: outcomes in 10 European centres. J Med Genet. 2009;46:254–8.
Fong PC et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34.
Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10:293–301.
Byrski T et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28:375–9.
Imyanitov EN. Breast cancer therapy for BRCA1 carriers: moving towards platinum standard? Hered Cancer Clin Pract. 2009;7:8.
American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397–406.
Culver J, Lowstuter K, Bowling L. Assessing breast cancer risk and BRCA1/2 carrier probability. Breast Dis. 2006;27:5–20.
Evans DG, Howell A. Breast cancer risk-assessment models. Breast Cancer Res. 2007;9:213.
Fasching PA, Bani MR, Nestle-Kramling C, Goecke TO, Niederacher D, Beckmann MW, et al. Evaluation of mathematical models for breast cancer risk assessment in routine clinical use. Eur J Cancer Prev. 2007;16:216–24.
Weitzel JN et al. Limited family structure and BRCA gene mutation status in single cases of breast cancer. Jama. 2007;297:2587–95.
Schwartz MD et al. Utilization of BRCA1/BRCA2 mutation testing in newly diagnosed breast cancer patients. Cancer Epidemiol Biomark Prev. 2005;14:1003–7.
Montgomery JL, Sanford LN, Wittwer CT. High-resolution DNA melting analysis in clinical research and diagnostics. Expert Rev Mol Diagn. 2010;10:219–40.
Mattocks CJ et al. Interlaboratory diagnostic validation of conformation-sensitive capillary electrophoresis for mutation scanning. Clin Chem. 2010;56:593–602.
ten Bosch JR, Grody WW. Keeping up with the next generation: massively parallel sequencing in clinical diagnostics. J Mol Diagn. 2008;10:484–92.
Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997;60:1013–20.
Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2:77–81.
Kurian AW, Sigal BM, Plevritis SK. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol. 2010;28:222–31.
Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. 2010;12:245–59.
Friedman LS et al. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet. 1995;57:1284–97.
Tonin P et al. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med. 1996;2:1179–83.
Neuhausen S et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996;13:126–8.
Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996;14:185–7.
Phelan CM, Kwan E, Jack E, Li S, Morgan C, Aube J, et al. A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families. Hum Mutat. 2002;20:352–7.
Frank TS et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10, 000 individuals. J Clin Oncol. 2002;20:1480–90.
Antoniou AC et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005;42:602–3.
Satagopan JM, Boyd J, Kauff ND, Robson M, Scheuer L, Narod S, et al. Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res. 2002;8:3776–81.
Berman DB, Wagner-Costalas J, Schultz DC, Lynch HT, Daly M, Godwin AK. Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds. Am J Hum Genet. 1996;58:1166–76.
Gorski B et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer. 2004;110:683–6.
Sokolenko AP et al. High frequency of BRCA1 5382insC mutation in Russian breast cancer patients. Eur J Cancer. 2006;42:1380–4.
Ramus SJ, Kote-Jarai Z, Friedman LS, van der Looij M, Gayther SA, Csokay B, et al. Analysis of BRCA1 and BRCA2 mutations in Hungarian families with breast or breast-ovarian cancer. Am J Hum Genet. 1997;60:1242–6.
Krajc M, Teugels E, Zgajnar J, Goelen G, Besic N, Novakovic S, et al. Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families. BMC Med Genet. 2008;9:83.
Couch FJ, Weber BL. Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Breast Cancer Information Core. Hum Mutat. 1996;8:8–18.
Ladopoulou A et al. Germ line BRCA1 & BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed. Cancer Lett. 2002;185:61–70.
Backe J et al. Frequency of BRCA1 mutation 5382insC in German breast cancer patients. Gynecol Oncol. 1999;72:402–6.
Caligo MA et al. BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations. Oncogene. 1996;13:1483–8.
Loginova Iu A, Nagornaia II, Shlykova SA, Petrova LI, Rybakova MV, Kuznetsova TV, et al. Molecular genetic analysis of Y-chromosome micro deletions in men with severe spermatogenic defects. Mol Biol (Mosk). 2003;37:74–80.
Oszurek O et al. Founder mutations in the BRCA1 gene in west Belarusian breast-ovarian cancer families. Clin Genet. 2001;60:470–1.
Tikhomirova L, Sinicka O, Smite D, Eglitis J, Hodgson SV, Stengrevics A. High prevalence of two BRCA1 mutations, 4154delA and 5382insC, in Latvia. Fam Cancer. 2005;4:77–84.
Pohlreich P et al. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. Breast Cancer Res. 2005;7:R728–36.
Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008;8:140.
Gronwald J, Elsakov P, Gorski B, Lubinski J. High incidence of 4153delA BRCA1 gene mutations in Lithuanian breast- and breast-ovarian cancer families. Breast Cancer Res Treat. 2005;94:111–3.
Janavicius R, Pepalyte I, Kucinskas V. Novel and common BRCA1 mutations in familial breast/ovarian cancer patients from Lithuania. Breast Cancer Res Treat. 2009;117:467–9.
Neuhausen SL et al. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet. 1996;58:271–80.
da Costa EC, Vargas FR, Moreira AS, Lourenco JJ, Caleffi M, Ashton-Prolla P, et al. Founder effect of the BRCA1 5382insC mutation in Brazilian patients with hereditary breast ovary cancer syndrome. Cancer Genet Cytogenet. 2008;184:62–6.
Simard J et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet. 1994;8:392–8.
Wagner TM, Moslinger R, Zielinski C, Scheiner O, Breiteneder H. New Austrian mutation in BRCA1 gene detected in three unrelated HBOC families. Lancet. 1996;347:1263.
Wagner TM et al. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer. 1998;77:354–60.
Baudi F et al. Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer. Hum Mutat. 2001;18:163–4.
Besic N, Cernivc B, de Greve J, Lokar K, Krajc M, Novakovic S, et al. BRCA2 gene mutations in Slovenian male breast cancer patients. Genet Test. 2008;12:203–9.
Krajc M, De Greve J, Goelen G, Teugels E. BRCA2 founder mutation in Slovenian breast cancer families. Eur J Hum Genet. 2002;10:879–82.
Nedelcu R et al. BRCA mutations in Italian breast/ovarian cancer families. Eur J Hum Genet. 2002;10:150–2.
Pisano M et al. Identification of a founder BRCA2 mutation in Sardinia. Br J Cancer. 2000;82:553–9.
Marroni F et al. Reconstructing the genealogy of a BRCA1 founder mutation by phylogenetic analysis. Ann Hum Genet. 2008;72:310–8.
Papi L et al. Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat. 2009;117:497–504.
Palmieri G et al. BRCA1 and BRCA2 germline mutations in Sardinian breast cancer families and their implications for genetic counseling. Ann Oncol. 2002;13:1899–907.
Palomba G et al. A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population. BMC Cancer. 2009;9:245.
Palomba G et al. Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital-based screening. Cancer. 2005;104:1172–9.
Russo A et al. BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat. 2007;105:267–76.
Russo A et al. 4843delC of the BRCA1 gene is a possible founder mutation in Southern Italy (Sicily). Ann Oncol. 2007;18 Suppl 6:vi99–vi102.
Calo V et al. A new germline mutation in BRCA1 gene in a sicilian family with ovarian cancer. Breast Cancer Res Treat. 2006;96:97–100.
Russo A et al. Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res Treat. 2009;113:67–70.
Malacrida S et al. BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy. J Clin Oncol. 2008;26:26–31.
Muller D, Bonaiti-Pellie C, Abecassis J, Stoppa-Lyonnet D, Fricker JP. BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect. Fam Cancer. 2004;3:15–20.
Stoppa-Lyonnet D et al. BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. Am J Hum Genet. 1997;60:1021–30.
Presneau N, Laplace-Marieze V, Sylvain V, Lortholary A, Hardouin A, Bernard-Gallon D, et al. New mechanism of BRCA-1 mutation by deletion/insertion at the same nucleotide position in three unrelated French breast/ovarian cancer families. Hum Genet. 1998;103:334–9.
Ghadirian P et al. The contribution of founder mutations to early-onset breast cancer in French-Canadian women. Clin Genet. 2009;76:421–6.
Diez O et al. Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat. 2003;22:301–12.
Diez O, Gutierrez-Enriquez S, Balmana J. Heterogeneous prevalence of recurrent BRCA1 and BRCA2 mutations in Spain according to the geographical area: implications for genetic testing. Fam Cancer. 2010;9:187–91.
Vega A et al. The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat. 2001;17:520–1.
Vega A, Torres M, Martinez JI, Ruiz-Ponte C, Barros F, Carracedo A. Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsula. Ann Hum Genet. 2002;66:29–36.
Diez O et al. Prevalence of BRCA1 and BRCA2 Jewish mutations in Spanish breast cancer patients. Br J Cancer. 1999;79:1302–3.
Campos B et al. Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain. Hum Mutat. 2003;21:452.
Infante M et al. BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin. Clin Genet. 2010;77:60–9.
Infante M et al. Two founder BRCA2 mutations predispose to breast cancer in young women. Breast Cancer Res Treat. 2010;122:567–71.
Duran M, Esteban-Cardenosa E, Velasco E, Infante M, Miner C. Mutational analysis of BRCA2 in Spanish breast cancer patients from Castilla-Leon: identification of four novel truncating mutations. Hum Mutat. 2003;21:448.
Beristain E, Martinez-Bouzas C, Mallabiabarrena G, Tejada MI. Is early onset breast cancer with no family history a good criterion for testing BRCA1 and BRCA2 genes? A small population-based study. Clin Genet. 2009;75:576–8.
Machado PM et al. Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes. J Clin Oncol. 2007;25:2027–34.
Peixoto A et al. The c.156_157insAlu BRCA2 rearrangement accounts for more than one-fourth of deleterious BRCA mutations in northern/central Portugal. Breast Cancer Res Treat. 2009;114:31–8.
Claes K, Poppe B, Coene I, Paepe AD, Messiaen L. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004;90:1244–51.
Peelen T et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet. 1997;60:1041–9.
Claes K, Machackova E, De Vos M, Poppe B, De Paepe A, Messiaen L. Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5+3A>G. Dis Markers. 1999;15:69–73.
Zeegers MP, van Poppel F, Vlietinck R, Spruijt L, Ostrer H. Founder mutations among the Dutch. Eur J Hum Genet. 2004;12:591–600.
Verhoog LC et al. Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer. 2001;37:2082–90.
Petrij-Bosch A et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997;17:341–5.
Hartmann C et al. Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families. Hum Mutat. 2004;24:534.
Engert S et al. MLPA screening in the BRCA1 gene from 1, 506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases. Hum Mutat. 2008;29:948–58.
Meindl A. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002;97:472–80.
Gorski B et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000;66:1963–8.
Foretova L et al. Genetic and preventive services for hereditary breast and ovarian cancer in the czech republic. Hered Cancer Clin Pract. 2006;4:3–6.
Ticha I, Kleibl Z, Stribrna J, Kotlas J, Zimovjanova M, Mateju M, et al. Screening for genomic rearrangements in BRCA1 and BRCA2 genes in Czech high-risk breast/ovarian cancer patients: high proportion of population specific alterations in BRCA1 gene. Breast Cancer Res Treat. 2010; doi:10.1007/s10549-010-0745-y.
Van Der Looij M et al. Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary. Int J Cancer. 2000;86:737–40.
Csokay B, Udvarhelyi N, Sulyok Z, Besznyak I, Ramus S, Ponder B, et al. High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history. Cancer Res. 1999;59:995–8.
Konstantopoulou I et al. Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients. Breast Cancer Res Treat. 2008;107:431–41.
Anagnostopoulos T et al. G1738R is a BRCA1 founder mutation in Greek breast/ovarian cancer patients: evaluation of its pathogenicity and inferences on its genealogical history. Breast Cancer Res Treat. 2008;110:377–85.
Loizidou M, Marcou Y, Anastasiadou V, Newbold R, Hadjisavvas A, Kyriacou K. Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus. Clin Genet. 2007;71:165–70.
Hadjisavvas A, Charalambous E, Adamou A, Neuhausen SL, Christodoulou CG, Kyriacou K. Hereditary breast and ovarian cancer in Cyprus: identification of a founder BRCA2 mutation. Cancer Genet Cytogenet. 2004;151:152–6.
Bergthorsson JT et al. BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age. J Med Genet. 2001;38:361–8.
Soegaard M et al. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark. Clin Cancer Res. 2008;14:3761–7.
Thomassen M et al. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. Acta Oncol. 2008;47:772–7.
Hansen TO, Jonson L, Albrechtsen A, Andersen MK, Ejlertsen B, Nielsen FC. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families. Breast Cancer Res Treat. 2009;115:315–23.
Harboe TL, Eiberg H, Kern P, Ejlertsen B, Nedergaard L, Timmermans-Wielenga V, et al. A high frequent BRCA1 founder mutation identified in the Greenlandic population. Fam Cancer. 2009;8:413–9.
Hansen TV et al. A common Greenlandic Inuit BRCA1 RING domain founder mutation. Breast Cancer Res Treat. 2009;115:69–76.
Einbeigi Z et al. A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer. 2001;37:1904–9.
Bergman A et al. A high frequency of germline BRCA1/2 mutations in western Sweden detected with complementary screening techniques. Fam Cancer. 2005;4:89–96.
Bergman A et al. The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation. Eur J Hum Genet. 2001;9:787–93.
Johannsson O et al. Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. Am J Hum Genet. 1996;58:441–50.
Johannsson O, Ranstam J, Borg A, Olsson H. BRCA1 mutations and survival in women with ovarian cancer. N Engl J Med. 1997;336:1255–6. author reply 1256–7.
Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001;93:1215–23.
Einbeigi Z, Meis-Kindblom JM, Kindblom LG, Wallgren A, Karlsson P. Clustering of individuals with both breast and ovarian cancer—a possible indicator of BRCA founder mutations. Acta Oncol. 2002;41:153–7.
Kremeyer B, Soller M, Lagerstedt K, Maguire P, Mazoyer S, Nordling M, et al. The BRCA1 exon 13 duplication in the Swedish population. Fam Cancer. 2005;4:191–4.
Hakansson S et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997;60:1068–78.
Einbeigi Z et al. Occurrence of both breast and ovarian cancer in a woman is a marker for the BRCA gene mutations: a population-based study from western Sweden. Fam Cancer. 2007;6:35–41.
Einbeigi Z, Enerback C, Wallgren A, Nordling M, Karlsson P. BRCA1 gene mutations may explain more than 80% of excess number of ovarian cancer cases after breast cancer—a population based study from the Western Sweden Health Care region. Acta Oncol. 2010;49:361–7.
Borg A, Dorum A, Heimdal K, Maehle L, Hovig E, Moller P. BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations. Dis Markers. 1999;15:79–84.
Moller P et al. Genetic epidemiology of BRCA1 mutations in Norway. Eur J Cancer. 2001;37:2428–34.
Moller P et al. Genetic epidemiology of BRCA mutations—family history detects less than 50% of the mutation carriers. Eur J Cancer. 2007;43:1713–7.
Rudkin TM, Hamel N, Galvez M, Hogervorst F, Gille JJ, Moller P, et al. The frequent BRCA1 mutation 1135insA has multiple origins: a haplotype study in different populations. BMC Med Genet. 2006;7:15.
Vehmanen P et al. Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum Mol Genet. 1997;6:2309–15.
Huusko P et al. Evidence of founder mutations in Finnish BRCA1 and BRCA2 families. Am J Hum Genet. 1998;62:1544–8.
Sarantaus L et al. Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur J Hum Genet. 2000;8:757–63.
Syrjakoski K et al. Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst. 2000;92:1529–31.
Sarantaus L, Auranen A, Nevanlinna H. BRCA1 and BRCA2 mutations among Finnish ovarian carcinoma families. Int J Oncol. 2001;18:831–5.
Paakkonen K et al. Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population. Genet Epidemiol. 2001;20:239–46.
Eerola H, Pukkala E, Pyrhonen S, Blomqvist C, Sankila R, Nevanlinna H. Risk of cancer in BRCA1 and BRCA2 mutation-positive and -negative breast cancer families (Finland). Cancer Causes Control. 2001;12:739–46.
Vahteristo P, Eerola H, Tamminen A, Blomqvist C, Nevanlinna H. A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families. Br J Cancer. 2001;84:704–8.
Syrjakoski K, Kuukasjarvi T, Auvinen A, Kallioniemi OP. CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer. 2004;108:475–6.
Hartikainen JM et al. Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ovarian cancer families. Clin Genet. 2007;72:311–20.
Lahti-Domenici J, Rapakko K, Paakkonen K, Allinen M, Nevanlinna H, Kujala M, et al. Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families. Cancer Genet Cytogenet. 2001;129:120–3.
Laurila E, Syrjakoski K, Holli K, Kallioniemi A, Karhu R. Search for large genomic alterations of the BRCA1 gene in a Finnish population. Cancer Genet Cytogenet. 2005;163:57–61.
Karhu R, Laurila E, Kallioniemi A, Syrjakoski K. Large genomic BRCA2 rearrangements and male breast cancer. Cancer Detect Prev. 2006;30:530–4.
Pylkas K, Erkko H, Nikkila J, Solyom S, Winqvist R. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families. BMC Cancer. 2008;8:146.
Thorlacius S et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996;13:117–9.
Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, et al. Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997;60:1079–84.
Johannesdottir G et al. High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res. 1996;56:3663–5.
Rafnar T et al. BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study. Eur J Cancer. 2004;40:2788–93.
Helgason A, Sigureth Ardottir S, Gulcher JR, Ward R, Stefansson K. mtDNA and the origin of the Icelanders: deciphering signals of recent population history. Am J Hum Genet. 2000;66:999–1016.
Scottish/Northern Irish BRCA1/BRCA2 Consortium. BRCA1 and BRCA2 mutations in Scotland and Northern Ireland. Br J Cancer. 2003;88:1256–62.
Liede A et al. Evidence of a founder BRCA1 mutation in Scotland. Br J Cancer. 2000;82:705–11.
Evans DG, Neuhausen SL, Bulman M, Young K, Gokhale D, Lalloo F. Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families. J Med Genet. 2004;41:e21.
Mazoyer S et al. The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. The BRCA1 Exon 13 Duplication Screening Group. Am J Hum Genet. 2000;67:207–12.
McDevitt TM et al. Spectrum and incidence of BRCA1 and BRCA2 mutations in the Republic of Ireland—An Audit (abstract). Eur J Hum Genet. 2009;17:195.
Menkiszak J et al. Hereditary ovarian cancer in Poland. Int J Cancer. 2003;106:942–5.
van Der Looij M, Wysocka B, Brozek I, Jassem J, Limon J, Olah E. Founder BRCA1 mutations and two novel germline BRCA2 mutations in breast and/or ovarian cancer families from North-Eastern Poland. Hum Mutat. 2000;15:480–1.
Perkowska M et al. BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland. Hum Mutat. 2003;21:553–4.
Ratajska M et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep. 2008;19:263–8.
Csokay B, Tihomirova L, Stengrevics A, Sinicka O, Olah E. Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Mutation in brief no. 258. Online. Hum Mutat. 1999;14:92.
Ozolina S et al. The 4154delA mutation carriers in the BRCA1 gene share a common ancestry. Fam Cancer. 2009;8:1–4.
Elsakov P et al. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet. 2010; doi:10.1111/j.1399-0004.2010.01404.x.
Krylova NY et al. BRCA1 4153delA founder mutation in Russian ovarian cancer patients. Hered Cancer Clin Pract. 2006;4:193–6.
Tamboom K, Kaasik K, Arsavskaja J, Tekkel M, Lilleorg A, Padrik P, et al. BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia. Hered Cancer Clin Pract. 2010;8:4.
Gayther SA, Harrington P, Russell P, Kharkevich G, Garkavtseva RF, Ponder BA. Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia. Am J Hum Genet. 1997;60:1239–42.
Tereschenko IV, Basham VM, Ponder BA, Pharoah PD. BRCA1 and BRCA2 mutations in Russian familial breast cancer. Hum Mutat. 2002;19:184.
Loginova AN, Pospekhova NI, Lyubchenko LN, Budilov AV, Zakhar’ev VM, Gar’kavtseva RF, et al. Spectrum of mutations in BRCA1 gene in hereditary forms of breast and ovarian cancer in Russian families. Bull Exp Biol Med. 2003;136:276–8.
Sokolenko AP et al. Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia. Fam Cancer. 2007;6:281–6.
Fedorova OE, Liubchenko LN, Paiadini Iu G, Kazubskaia TP, Amosenko FA, Gar’kavtseva RF, et al. Analysis of BRCA1/2 and CHEK2 mutations in ovarian cancer and primary multiple tumors involving the ovaries. Patients of Russian population using biochips. Mol Biol (Mosk). 2007;41:37–42.
Cvok ML, Cretnik M, Musani V, Ozretic P, Levanat S. New sequence variants in BRCA1 and BRCA2 genes detected by high-resolution melting analysis in an elderly healthy female population in Croatia. Clin Chem Lab Med. 2008;46:1376–83.
Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE. An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res. 2007;9:104.
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Janavičius, R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA Journal 1, 397–412 (2010). https://doi.org/10.1007/s13167-010-0037-y