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.