The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation

The most recurrent BRCA1/BRCA2 mutation in Sweden is the BRCA1 mutation 317 1ins5. In the western part of Sweden this mutation accounts for as much as 77% of identified mutations in these two genes. Our aim was to analyse in d etail the haplotype and founder effects of the 3171insS and furthermore att empt to estimate the time of origin of the mutation. In the study we includ ed eighteen apparently unrelated families with hereditary breast and/or ova rian cancer. At least one individual in each family had previously tested p ositive for the 3171ins5 mutation. Polymorphic microsatellite markers were used for the haplotype analyses. The markers were located within or flankin g the BRCA1 gene spanning a region of 17.3 cm. We found several different h aplotypes both for disease alleles and for the normal alleles. However, a c onserved haplotype of 3.7 cm was observed in the 3171ins5 carriers spanning over four markers located within or very close to the BRCA1 gene. As this haplotype was not present in any of the normal controls it is highly likely that this is a mutation identical by descent, i.e. a true founder. The res ults from the haplotype analyses were used to estimate the age of the mutat ion. Estimations based on the P-excess and linkage disequilibrium gives a f irst appearance of the mutation sometime around the 6th century, approximat ely 50 generations ago.