title: The Norwegian founder mutations in BRCA1: high penetrance confirmed in an incident cancer series and differences observed in the risk of ovarian cancer.
abstract: We aimed to describe the penetrances of the four Norwegian founder mutations in BRCA1 (816delGT, 1135insA, 1675delA and 3347delAG) with regard to breast and ovarian cancers in families ascertained through cancer family clinics or a consecutive series of women with breast or ovarian cancer. We have extended the families as far as possible and tested all family members that asked for genetic testing. Penetrance is based upon counting the mutation carriers. The series contains sufficient numbers of mutation carriers to minimise variation in the estimates due to a limited sample set. The penetrances for all four mutations were high, both with respect to breast and ovarian cancers. This is in accordance with other reports from cancer family clinics, but contrasts with reports from population-based series of mutation carriers. Risks of first cancer (breast or ovarian), breast cancer, and ovarian cancer at age 50 years were 43, 30 and 17%, respectively. Corresponding risks at age 70 years were 84, 58 and 58%. Risks for breast cancer before age 30 years and for ovarian cancer before 35 years were low. Penetrances with regard to ovarian cancer were different for the four mutations. The risk of ovarian cancer was doubled in carriers of the 1675delA mutation when compared with the 816delGT mutation (24 versus 12% at age 50 years, P=0.004). The mutations analysed are high penetrance alleles. No differences in penetrance between the series ascertained through the cancer family clinic or the series of consecutive cancer patients was observed. There are discrepancies between our findings and the low penetrances reported for other mutations in other populations. This may be due to methodological differences, but may reflect differences between mutations and/or modifying factors in different populations.
authors.affiliation: Section of genetic counseling, Department of Cancer Genetics, Norwegian Radium Hospital, N-0310 Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Heimdal
authors.forename: L
authors.initials: L
authors.lastname: Maehle
authors.forename: J
authors.initials: J
authors.lastname: Apold
authors.forename: J C
authors.initials: JC
authors.lastname: Pedersen
authors.forename: P
authors.initials: P
authors.lastname: Møller
mesh_terms: D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009664:Norway / Q000453:epidemiology; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D018570:Risk Assessment; D012307:Risk Factors