title: Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy.
abstract: BACKGROUND
  Germline mutations in the BRCA1 and BRCA2 tumour-suppressor genes predispose to early-onset breast and ovarian cancer. Although both genes display a highly heterogeneous mutation spectrum, a number of alterations recur in some populations. Only a limited number of founder mutations have been identified in the Italian population so far.
  
  
  OBJECTIVE
  To investigate the spectrum of BRCA1/BRCA2 mutations in a set of families originary from the Central-Eastern part of Tuscany and to ascertain the presence of founder effects. We also wanted to approximate the age of the most frequent BRCA1 founder mutation.
  
  
  RESULTS
  Overall, four distinct BRCA1 mutations accounted for a large fraction (72.7%) of BRCA1-attributable hereditary breast/ovarian cancer in families originary from this area. We identified common haplotypes for two newly recognised recurrent BRCA1 mutations, c.3228_3229delAG and c.3285delA. The c.3228_3229delAG mutation was estimated to have originated about 129 generations ago. Interestingly, male breast cancer cases were present in 3 out of 11 families with the c.3228_3229delAG mutation.
  
  
  CONCLUSIONS
  The observation that a high proportion of families with BRCA1 alterations from Central-Eastern Tuscany harbours a limited number of founder mutations can have significant impact on clinical management of at risk subjects from this area. In addition, the identification of a large set of families carrying an identical mutation that predisposes to breast and ovarian cancer provides unique opportunities to study the effect of other genetic and environmental factors on penetrance and disease phenotype.
authors.affiliation: Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy. l.papi@dfc.unifi.it
authors.forename: Laura
authors.initials: L
authors.lastname: Papi
authors.forename: Anna Laura
authors.initials: AL
authors.lastname: Putignano
authors.forename: Caterina
authors.initials: C
authors.lastname: Congregati
authors.forename: Ines
authors.initials: I
authors.lastname: Zanna
authors.forename: Francesco
authors.initials: F
authors.lastname: Sera
authors.forename: Doralba
authors.initials: D
authors.lastname: Morrone
authors.forename: Mario
authors.initials: M
authors.lastname: Falchetti
authors.forename: Marco Rosselli Del
authors.initials: MR
authors.lastname: Turco
authors.forename: Laura
authors.initials: L
authors.lastname: Ottini
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010375:Pedigree