Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Jan 10:16:3.
doi: 10.1186/s13053-017-0085-6. eCollection 2018.

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

Cecilie Heramb  1   2   3 , Teresia Wangensteen  1 , Eli Marie Grindedal  1 , Sarah Louise Ariansen  1 , Sheba Lothe  4 , Ketil Riddervold Heimdal  1 , Lovise Mæhle  1
Affiliations

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

Cecilie Heramb et al. Hered Cancer Clin Pract. .

Abstract

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.

Keywords: BRCA1; BRCA2; Founder mutations; Genetic testing.

PubMed Disclaimer

Conflict of interest statement

The study was carried out in the Section of Hereditary Cancer, Department of Medical Genetics, Oslo University Hospital, OUH, and was approved by the Data Protection Officer at OUH as a quality of care study. All activities fulfilled the requirements of genetic counselling, information and consent stated by the Norwegian Act on Biotechnology, as part of the health service.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Proportions of BRCA1 mutation carriers vs frequency of mutations (N = 2432)
Fig. 2
Fig. 2
Proportions of BRCA2 mutation carriers vs frequency of mutations (N = 1092)
See this image and copyright information in PMC

References

    1. Levy-Lahad E, Friedman E. Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2007;96(1):11–15. doi: 10.1038/sj.bjc.6603535. - DOI - PMC - PubMed
    1. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117–1130. doi: 10.1086/375033. - DOI - PMC - PubMed
    1. Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105(11):812–822. doi: 10.1093/jnci/djt095. - DOI - PubMed
    1. Edwards SM, Evans DG, Hope Q, Norman AR, Barbachano Y, Bullock S, et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010;103(6):918–924. doi: 10.1038/sj.bjc.6605822. - DOI - PMC - PubMed
    1. Iqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2012;107(12):2005–2009. doi: 10.1038/bjc.2012.483. - DOI - PMC - PubMed