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

BACKGROUND: Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation-screening. A key property of eligibility criteria is the tradeoff between the number of mutation-carriers identified versus population-members tested. We assess the fractions of mutation-carriers identified, versus women undergoing mutation-testing, for BRCA1/2 founder-mutation-screening in US Ashkenazi-Jewish women. METHODS: BRCA1/2 carrier-probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation-carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0%-10%, we compared the percent of founder-mutations detected vs. the percent of women requiring mutation-testing. PCR mutation-testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2). RESULTS: Identifying 90% of BRCA1/2 founder-mutations required testing the 60% of Ashkenazi-Jewish women with carrier-probabilities exceeding 0.56%, potentially avoiding mutation-testing for approximately 0.7-1.1 million US Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier-probability exceeded 0.78% identified 80% of mutation-carriers, increasing to 89% of mutation-carriers when accounting for cascade-testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds; e.g., a 5% threshold identified 46% of mutation-carriers while testing 10% of women. CONCLUSIONS: Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation-carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder-mutation-carriers, without testing ~1 million US Ashkenazi-Jewish women with lowest carrier-probabilities. IMPACT: In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation-screening.