Background and Aims:
Germline mutations in BRCA1 and BRCA2 confer high lifetime risk of breast and ovarian cancer but importantly these risks are not irreversible. Identification of asymptomatic carriers could significantly reduce the incidence of these diseases. The traditional model of familial cancer practice involves ascertaining high-risk individuals based on family history but >50% of women who carry a BRCA1/2 mutation may not have a family history of cancer. Momentum toward genetic screening of the asymptomatic population is growing but it remains unclear what is the true frequency of actionable mutations in the general western population and the extent to which the public would accept such screening, particularly for those individuals identified with an actionable mutation in the absence of an overt family history.
Methods:
We are sequencing the entire coding regions of 20 known or proposed HBOC genes in 5,000 cancer-free Australian women recruited from the lifepool study (www.lifepool.org). The data was filtered to identify all clinically “actionable” mutations.
Results:
To date, data from 2,900 women has identified 23 with actionable mutations in BRCA1 (5 mutations), BRCA2 (13 mutations) or PALB2 (5 mutations). All 17 women subsequently accepted an invitation to attend a Familial Cancer Centre and proceeded to formal clinical genetic testing and risk mitigation. In addition 7 women had pathogenic mutations in BRIP1, RAD51C or RAD51D.
Conclusions:
Our unique pilot data directly demonstrates a population carrier frequency of ~1% for actionable mutations in these recognized breast and/or ovarian cancer predisposition genes and that such testing is well accepted by the screened population.