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

Abstract

The most recurrent BRCA1/BRCA2 mutation in Sweden is the BRCA1 mutation 3171ins5. 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 detail the haplotype and founder effects of the 3171ins5 and furthermore attempt to estimate the time of origin of the mutation. In the study we included eighteen apparently unrelated families with hereditary breast and/or ovarian cancer. At least one individual in each family had previously tested positive for the 3171ins5 mutation. Polymorphic microsatellite markers were used for the haplotype analyses. The markers were located within or flanking the BRCA1 gene spanning a region of 17.3 cM. We found several different haplotypes both for disease alleles and for the normal alleles. However, a conserved 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 results from the haplotype analyses were used to estimate the age of the mutation. Estimations based on the P excess and linkage disequilibrium gives a first appearance of the mutation sometime around the 6th century, approximately 50 generations ago. European Journal of Human Genetics (2001) 9, 787 ± 793.

Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy

“…Should an increased risk of male breast cancer associated with the c.3228_3229delAG sequence variant be confirmed, it would be appropriate to consider offering appropriate surveillance to male carriers of this mutation. G1738R 11 Greece [27] 3171ins5 (18) 50 South Sweden [11] 3744delT (8) 23-36 Finland [28] 4216-2A[G (9) \10 Finland [28] 2804delAA (19) 32 (15-49) Netherlands [29] 185delAG (17) 46 (23-80) Ashkenazi Jews [30] 4184del4 (6) 170 (70-350) [30] 5382insC (19) 38 ( …”

“…We used haplotypes for the nine 17q21 microsatellite markers in affected and unaffected chromosomes, with the following parameters: (a) chromosome map distances derived from the Marshfield and/or Genéthon sex-average genetic maps (URL: http://www.ncbi.nlm.nih.gov/map view/) and by Bergman et al [11]; (b) population growth rate: 0.054; (c) proportion of mutation-carrying chromosomes sampled: 0.00698.…”

BRCA1 and BRCA2 Mutations in the Ovarian Cancer Population across Race and Ethnicity: Special Reference to Asia

“…The most common mutation found in Sweden is BRCA1-3171insC, accounting for 70% of the mutations in the BRCA1/2 genes. It is thought to have originated about 50 generations ago [24,25]. …”

A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect

“…The age of the 3-bp deletion was estimated using previously described methods [11,12]. By comparing marker allele frequencies in mutation carrying and normal chromosomes, the linkage equilibrium index between each marker and the mutation was calculated as δ= (P m −P n /1−P n ), where P m is the frequency of the marker allele on the mutation-bearing chromosomes and P n is the frequency of the same allele on normal chromosomes.…”