Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families

The 999del5 mutation is the single, strong BRCA2 founder mutation in Icelan d and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in F inland, we constructed haplotypes with polymorphic markers within and flank ing the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast c ancer families. All Icelandic families analysed shared a common core haplot ype of about 1.7 cM. The common ancestors for the Icelandic families studie d were estimated to trace back to 340-1000 years, not excluding the possibi lity that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southw estern Finland, shared a four-marker (0.5 cM) core haplotype with the Icela ndic 999del5 haplotype. A distinct similar to 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, i n the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a comm on ancient origin for the 999del5 mutation in Iceland and in Finland, but d istinct mutational events cannot be ruled out. The surprising finding of th e same mutation in two completely different haplotypes in a sparsely popula ted area in Finland may suggest gene conversion.