Founder mutation in the BRCA1 gene in Malay breast cancer patients from Singapore

The mutation spectrum of the BRCA1 gene among ethnic groups from Asia has not been well studied. We investigated the frequency of mutations in the BRCA1 gene among Malay breast cancer patients from Singapore, independent of family history. By using the protein truncation test (PTT) and direct sequencing, BRCA1 mutations were detected in 6 of 49 (12.2%) unrelated patients. Four novel missense mutations in exon 11, T557A (1788A>G), T582A (1863A>G), N656S (2086A>G) and P684S (2169C>T) were identified in one patient. Two patients had missense mutations in exon 23, V1809A (5545T>C), which has been previously detected in individuals from Central and Eastern Europe. Three unrelated patients had the deleterious 2846insA frameshift mutation in exon 11. Methylation specific PCR (MSP) of the promoter region of the BRCA1 gene detected hypermethylation of tumor DNA in an additional 2 patients. Haplotype analysis using the microsatellite markers D17S855, D17S1323 and D17S1325 revealed a common haplotype for the three unrelated patients and their three relatives with the 2846insA mutation. These findings strongly suggest that the 2846insA mutation, the most common deleterious mutation in this study, may possibly be a founder mutation in breast cancer patients of Malay ethnic background.