On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

Abstract

The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual. Using a maximum likelihood method that allows for both recombination and mutational events of marker loci, we estimated that the mutation arose some 1800 years ago in either Scandinavia or what is now northern Russia and subsequently spread to the various populations we genotyped during the following centuries, including the AJ population. Age estimates and the molecular evolution profile of the most common linked haplotype in the carrier populations studied further suggest that c.5266dupC likely entered the AJ gene pool in Poland approximately 400-500 years ago. Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.

Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations

“…The BRCA1 c.5266dupC mutation (also known as 5382insC) was the most prevalent mutation identified in this study. This Ashkenazi Jewish founder mutation [34,35] has been described in Dutch, Russian, French and many other populations, and a recent study showed that 245 carriers from 14 different populations presented the same haplotype, suggesting a single founder origin [36]. Indeed, this is one of the most common mutations identified in Brazilian patients to date [22,24,25], and Gomes et al [22] found 5382insC in 56% of all BRCA mutation carriers, and a very similar frequency (57%) was described by Lourenço et al [37].…”

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

“…To estimate the age of the mutation (or, more precisely, the number of generations as the most recent common ancestor (MRCA) of the 185delAG carriers), we used the method that was first used to estimate the age of several BRCA1 mutations, including the mutation that is the focus of the present study, 185delAG* BRCA1, 18 and then extended and applied to BRCA2 mutations, 28 and which has been used in several other similar studies, most recently in an analysis of the mutation BRCA1*c.5266dupC (5382insC). 29 This method uses maximum likelihood and allows for both recombination and mutational events at the marker loci as means of altering a presumed ancestral haplotype. Phased haplotypes were used if these could be inferred from available family data; otherwise, all possible haplotypes were constructed from multi locus genotype data and weighted according to their probability.…”

Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia

“…c.5266dupC mutation is the most prevalent BRCA1 mutation in Europe. It was originally described as founder mutation in the Ashkenazi Jewish population (Roa et al, 1996) but recently its origin was revealed as north European and it entered the Ashkenazi gene pool about 400-500 years ago (Hamel et al, 2011). BRCA1 mutations c.843_846delCTCA, c.1687C > T, c.5251C > T and c.676delT and BRCA2 mutation c.9371A > T were found in several nearby countries.…”