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This is very informative and up-to-date single reference for all (women and men) who are at increased genetic risk due to BRCA1/2 mutations, as well as clinicians dealing with these patients.

This source i’ll definitely now include in my recommendations for high risk women, along with FORCE and a free gift of Liv Breast Self-Exam Kit kindly provided by Association for Hereditary Cancer (PVAS).

Several founder mutations in BRCA1/2 have been identified in Holland [94], 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 [92]. 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 [95]. 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Slightly outdated (as of year 2002) list of published and unpublished BRCA1/2 mutations in Netherlands and Belgium can be found at http://www.humgen.nl/lab-devilee/Lab/b1nlmuts.htm.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 [96], which can be easily detected by multiplex-ligation dependent probe amplification (MLPA) method.

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Claes et al. [91] 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 [91]. BRCA1 c.2359dupG and BRCA2 c.516+1G>A have not yet been reported in other populations.

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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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].

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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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 [79].

Diez et al., [80] 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 [81]. It was also found in French and British families of Spanish origin [82].

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 [83]. Some data indicate an unique origin of reported BRCA2 exon 23 mutation BRCA2 c.9026_9030del5 in Catalan families (North-East Spain) [84]. 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 [88].

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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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 [75]. 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 [6].

The BRCA1 c.5030_5033delCTAA (BIC: 5149delCTAA) [76] and c.3839_3843delinsAGGC (BIC: 3958delCTCAGinsAGGC) [77] mutations were reported in at least three independent families from France.

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 [78]. 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 [6].

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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In Italy, 4–27% of the identified mutations recurred among apparently unrelated families, and significant regional founder effect has been demonstrated for few mutations [63–66].

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) [65].

In Sardinia, contribution of BRCA1/2 mutations to breast cancer predisposition has been reported for populations from the Northern part of the island [67], 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 [68]. Conversely, previously regarded as another founder mutation, BRCA2 3950_3952delTAGinsAT was found instead running in families belonging to a single extended pedigree [68].

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. [74] 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 [74]. The founder c.5062_5064delGTT mutation accounts for 15% (9/61) of families with small BRCA1 mutations.

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

TBC