A Pragmatic Testing-Eligibility Framework for Population Mutation Screening: The Example of BRCA1/2

Area of Science:

• Genetics
• Population Screening
• Risk Assessment

Background:

• Genetic testing eligibility criteria require reevaluation due to technological advancements and cost reductions.
• The balance between identified mutation carriers and tested individuals is crucial for screening protocols.
• This study focuses on BRCA1/2 founder mutations within the U.S. Ashkenazi-Jewish population.

Purpose of the Study:

• To evaluate the tradeoff between identifying BRCA1/2 founder mutation carriers and the number of women undergoing genetic testing in the Ashkenazi-Jewish population.
• To assess the effectiveness of different carrier probability thresholds for optimizing screening strategies.

Main Methods:

• Utilized the BRCAPRO tool to calculate carrier probabilities for 4,589 participants in the Washington Ashkenazi Study.
• Compared the percentage of founder mutations detected against the percentage of women tested at various carrier probability thresholds (0-10%).
• Conducted PCR mutation testing for three specific Ashkenazi-Jewish founder mutations in BRCA1 and BRCA2 genes.

Main Results:

• Testing 60% of women with a carrier probability >0.56% identified 90% of BRCA1/2 founder mutations, potentially sparing 0.7-1.1 million women from testing.
• A threshold of 0.78% carrier probability tested 44% of women, identified 80% of carriers (89% with cascade testing).
• A 5% carrier probability threshold identified 46% of carriers while testing only 10% of the population.

Conclusions:

• Varying carrier probability thresholds offer distinct tradeoffs between identifying mutation carriers and the number of women tested.
• Lower thresholds are effective in identifying a high percentage of BRCA1/2 founder mutation carriers while minimizing the number of women undergoing genetic testing.