BACKGROUND

Founder mutations in the two breast cancer genes, and , 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 founder mutations were defined by haplotyping in 2001, and accounted for 68% of mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both and in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the carrier population of the largest clinic of hereditary cancer in Norway.

METHODS

A total of 2430 carriers from 669 different families, and 1092 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 and 87 different variants among the mutation carriers. Forty-six per cent of the registered families (454/981) had a previously reported Norwegian founder mutation. The majority of mutations (71%) were rare, each found in only one or two families. Fifteen per cent of families and 25% of families had one of these rare variants. The four well-known Norwegian founder mutations previously confirmed through haplotyping were still the four most frequent mutations in carriers, but the proportion of 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 and 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.