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 ].