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Background  Founder mutations in the two breast cancer genes,  BRCA1  and  BRCA2 , have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian  BRCA1  founder mutations were defined by haplotyping in 2001, and accounted for 68% of  BRCA1  mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both  BRCA1  and  BRCA2  in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the  BRCA1/2  carrier population of the largest clinic of hereditary cancer in Norway.    Methods  A total of 2430  BRCA1  carriers from 669 different families, and 1092  BRCA2  carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.    Results  There were 120 different  BRCA1  and 87 different  BRCA2  variants among the mutation carriers. Forty-six per cent of the registered  BRCA1/2  families (454/981) had a previously reported Norwegian founder mutation. The majority of  BRCA1/2  mutations (71%) were rare, each found in only one or two families. Fifteen per cent of  BRCA1  families and 25% of  BRCA2  families had one of these rare variants. The four well-known Norwegian  BRCA1  founder mutations previously confirmed through haplotyping were still the four most frequent mutations in  BRCA1  carriers, but the proportion of  BRCA1  mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.    Conclusions  The spectrum of  BRCA1  and  BRCA2  mutations in the carrier population at Norway’s largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.

BRCA1 and BRCA2 mutation spectrum – an update on mutation distribution in a large cancer genetics clinic in Norway