Novel germline BRCA1 mutations detected in women in Singapore who developed breast carcinoma before the age of 36 years

BACKGROUND. In recent years, although BRCA1 has been extensively investigat ed, the contribution of inherited BRCA1 mutations to breast carcinoma in As ian populations is largely unknown. The authors undertook this study to det ermine the prevalence and spectrum of germline BRCA1 mutations among women in Singapore with early onset breast carcinoma. METHODS. Forty-three of 72 eligible patients whose breast carcinoma was dia gnosed before the age of 36 years were studied, independent of family histo ry. DNA samples from 50 unrelated individuals randomly selected from the Na tional Thalassemia Registry served as controls. Mutational screening was pe rformed by single-strand conformation polymorphism analysis and protein tru ncation test, and alterations were confirmed by sequencing. First-degree re latives of patients with definite BRCA1 mutations were offered screening. RESULTS. A total of 6 novel alterations in BRCA1 were identified, including 2 frameshift mutations in exon II (2846insA and 2885delA), 3 rare sequence variants, and I polymorphism. Three women (7%) carried deleterious mutatio ns, and the mutation was present in at least 1 unaffected first-degree rela tive of the proband. The same mutation (2846insA) was identified in 2 of th e 7 unrelated subjects of Malay ethnicity. One mutation and three rare Vari ants were identified in four women with no family history of breast or ovar ian carcinoma whereas all women with affected first-degree relatives did no t harbor BRAC1 mutations. No mutation was identified in the controls. CONCLUSIONS. The spectrum of germline BRCA1 mutations among the patients in this study was distinct from that in Caucasian populations although a simi lar prevalence was observed. Larger studies are necessary to clarify the si gnificance of the mutation 2846insA in the Malay community and the penetran ce of specific mutations in the Singapore population. (C) 2000 American Can cer Society.