To Reflex or Not: Additional BRCA1/2 Testing in Ashkenazi Jewish Individuals Without Founder Mutations

Abstract

This study determined the prevalence of non-Ashkenazi Jewish BRCA1/2 mutations in the Ashkenazi Jewish population in the state of Michigan, current provider testing practices, and the use of mutation probability models in determining which Ashkenazi Jewish individuals should be offered further analysis following negative BRCA1/2 founder testing. Testing patterns, mutation probabilities, and testing results were assessed for 327 Ashkenazi Jewish individuals seen for BRCA1/2 counseling in the state of Michigan who underwent testing for the Ashkenazi Jewish founder mutations. Only one (0.6 %) Ashkenazi Jewish individual with sequencing after negative founder analysis was found to have a non-founder mutation; no rearrangements were identified. Testing patterns varied by clinic, with the proportion of Ashkenazi Jewish individuals undergoing additional sequencing ranging from 22.2 to 92.9 %. In Ashkenazi Jewish individuals with a pre-test BRCAPRO risk calculation, the mean risk was significantly higher in those with follow-up sequencing compared to those who did not pursue additional testing. The low prevalence of non-founder BRCA1/2 mutations in Ashkenazi Jewish individuals does not warrant automatically reflexing to full analysis after negative mutation testing. Increased use of mutation probability models may aid in determining which cases warrant additional testing.

Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient?

“…A study by Petrucelli et al [13] on the Ashkenazi Jewish population of Michigan found that only 1 out of 166 (0.6%) had a non-founder BRCA1/2 mutation. [13] The authors observed that the National Comprehensive Cancer Network recommends further molecular analysis following a negative founder mutation result only when there is evidence of non-Ashkenazi Jewish ancestry.…”

“…[13] The authors observed that the National Comprehensive Cancer Network recommends further molecular analysis following a negative founder mutation result only when there is evidence of non-Ashkenazi Jewish ancestry. Even though only a small number of counsellees from the current study opted for further analysis when initial founder mutation testing was negative, 40% (4/10) had a non-founder mutation, which is a higher proportion than reflected in Petrucelli et al 's research.…”

Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center

“…17 Online surveys of cancer genetics providers have demonstrated that providers use various tools to make decisions regarding reflex testing, including family history, risk calculation based on probability models (eg, the BRCAPRO model, 24 the Myriad II model [Myriad Genetics Inc, Salt Lake City, Utah], 25 and the Tyrer-Cuzick model 26 ), the NCCN and US Preventive Services Task Force criteria, institutional criteria, insurance criteria, or review on a case-by-case basis. The literature suggests wide variation in the rates of reflex sequencing among these patients, ranging from 22% to 93%.…”

“…17 Online surveys of cancer genetics providers have demonstrated that providers use various tools to make decisions regarding reflex testing, including family history, risk calculation based on probability models (eg, the BRCAPRO model, 24 the Myriad II model [Myriad Genetics Inc, Salt Lake City, Utah], 25 and the Tyrer-Cuzick model 26 ), the NCCN and US Preventive Services Task Force criteria, institutional criteria, insurance criteria, or review on a case-by-case basis. 17 Insurance criteria often play a critical role in decision making because many insurance providers mandate that AJ patients undergo founder mutation testing first and some do not offer coverage for other testing strategies. Although the above mentioned surveys address the use of reflex testing, to the best of our knowledge, patterns of genetic practitioners' use of comprehensive multigene panels in AJ patients as initial screening have not been reported.…”

“…There is a Cancer March 1, 2019 growing body of literature evaluating the prevalence of nonfounder BRCA1/2 mutations in AJ patients, with reported rates ranging from 0.3% to 0.8%. 9,[15][16][17] Rosenthal et al reviewed what to our knowledge is the largest cohort to date of nearly 40,000 AJ patients, and identified nonfounder BRCA1/2 mutations in approximately 0.8% of the population. 18 Nonfounder BRCA1/2 mutations comprised 8.5% of all BRCA1/2 mutations in this group.…”