Abstract

A large number of cancer predisposing BRCA1/BRCA2 mutations have been reported, with a wide variety among populations. In some restricted groups, specific germline mutations in these tumor suppressor genes have been found with high predominance, due to a founder effect.

We focused our review on the Italian founder mutations.

The first Italian BRCA1 founder mutation, 5083del19, was found in Calabria: the presence of common allele in all carriers of this mutation (also in families with Calabrian origin living in other parts of Italy) confirmed its founder effect. The same BRCA1 mutation was identified in the Sicilian population, but only the haplotype analysis can reveal the common ancestor of these groups. Another BRCA1 founder mutation, 4843delC, was found in Sicily. Four distinct BRCA1 mutations are attributable to families original from Tuscany: 3348delAG, 3285delA, 1499insA and 5183delTGT; the latter has been shown to be a founder mutation from North-Eastern Italy. The first BRCA2 mutation was identified in Sardinia, 8765delAG, a mutation already described as a founder mutation in Jewish-Yemenite families and also in French-Canadian population but with independent origins of carriers in these three populations. BRCA2 3951del3 and BRCA1 917delTT have been described as founder mutations in Middle Sardinia and in South and Middle Sardinia, respectively.

Studies regarding prevalence and penetrance of founder mutations can allow to quantify the degree of homogeneity within a population and can surely help the geneticist and oncologist to simplify their choices in the genetic testing on high-risk families, on the basis of their ethnical origin.

Keywords: BRCA1, BRCA2, founder mutation, Italian BRCA1, BRCA2 3951del3, BRCA1 917delTT, BRCA1 5083del19, BRCA1 3348delAG, BRCA2 8765delAG, BRCA1 Val1688del