Founder mutation (BRCA1 185delAG and 5382insC, BRCA2 6174delT)

In a population study of about 3,000 Ashkenazi Jewish individuals unselected for breast cancer, the BRCA1 185delAG mutation had a carrier frequency of 1.09 percent and 5382insC 0.13 percent, and in 3,085 individuals the BRCA2 6174delT mutation 1.52 percent, confirming 185delAG and 6174delT as the two most frequent alleles predisposing to hereditary breast cancer among the Ashkenazim and suggesting lower penetrance for 6174delT (Roa 1996). Among 5,318 Jewish volunteers in Washington, 120 carriers of one of the three mutations were identified; by age 70 the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval 40 to 73), of ovarian cancer 16 percent and of prostate cancer 16 percent, with no difference between BRCA1 and BRCA2 carriers and risks well below the 85 percent estimated from high-risk families (Struewing 1997). Because the combined frequency exceeds 2 percent, testing for the three variants is informative in this population without a family history, and NICE CG164 lists Jewish ancestry among the features for which clinicians should seek advice from a specialist genetics service and asks clinics to record ethnic background when assessing carrier probability; Cancer Research UK's family history page names a Jewish background as a reason the clinic may consider testing more likely to be useful. BRCA1 founder mutations matter for triple-negative disease because BRCA1-associated cancers are mostly basal-like and triple-negative (Atchley 2008). Other populations have their own founder alleles; the history on the parent page records the Polish BRCA1 variants beside the Ashkenazi ones.