BRCA1 R841W - A STRONG CANDIDATE FOR A COMMON MUTATION WITH MODERATE PHENOTYPE

BRCA1 mutations cause increased risk for breast and ovarian cancer, fr equently of early onset. Many different mutations occur in BRCA1, incl uding several examples of recurrent mutations, each of which accounts for a significant number of families with heritable cancer predisposit ion. These common mutations have an etiological role in many breast an d ovarian cancer cases and provide the opportunity to examine genotype -phenotype correlations and genotype-environment interactions in indiv iduals with the identical BRCA1 lesion. We report a novel missense cha nge in BRCA1, 2640 C-->T (R841W), found in 3 cases from a subject grou p of 305 breast and 79 ovarian cancer cases from Orange County, CA. Th ese are consecutive, population-based cases not selected for age or fa mily history. In all three cases, there is a strong family history of breast, ovarian, or other cancers possibly related to a BRCA1 defect a nd family members showed a high concordance of cancer incidence with t he presence of R841W. The age of cancer onset was not always distinct from typical sporadic cases. Testing of a sample of 413 unrelated indi viduals to examine the hypothesis that R841W might be a rare polymorph ism detected one additional instance in a woman with breast cancer dia gnosed at age 77 years, and cancer in one parent R841W is likely to be an etiologically significant lesion with involvement in close to 1% ( 95% confidence interval of 0-1.7%) of all breast and ovarian cancers i n this population. (C) 1996 Wiley-Liss, Inc.