A report of novel inactivating missense mutations of BRCA1 detected in patients with acute myeloid leukemia.

Exon 11 and exon 14 of BRCA1, a tumor suppressor gene, are known to be mutated in various cancers. We screened 24 samples (13 from patients with acute myeloid leukemia and 11 from normal controls) using polymerase chain reaction to detect BRCA1 exon 11 and exon 14 mutations, if any. Purified polymerase chain reaction-amplified products of four samples (cases 1-4) were subjected to bidirectional sequence analysis. The sequence analysis revealed in total 20 mutations. One novel frameshift mutation, that is, c.2339insG (p.E781fs), observed in case 1 promoted the synthesis of truncated protein (protein 1). In case 2, five novel insertions mutations c.2376insC (p.K793fs), c.2380insT (p.A794fs), c.2443insT (p.I815fs), c.2533insG (p.I845fs), and c.2511insG (p.N838fs), two novel deletion mutations, c.3762delG (p.N1255fs) and c.3830delC (p.A1277fs), along with one reported mutation,c.3621delG (p.Lys1208fs), were observed which resulted in a truncated protein (protein 2). Besides these, one nonsense c.2383A > T (p.K795X), and four missense c.2429A > C (p.N810T), c.2430C > A (p.N810K), c.3644A > T (p.N1215I), and c.3740 T > A (p.V1247D) were also observed in case 2. In case 3, a single missense c.3577 T > C (p.F1193L) and three silent mutations c.3576 T > C (p.P1192P), c.3579C > T (p.F1193F), and c.4311 T > C (p.S1437S) were noted, having no impact on the encoded protein's function. However, a unique silent mutation c.4252 T > C (p.L1418L)  observed in case 4 did not influence the protein sequence. Bioinformatics analysis revealed that both truncated proteins (protein 1 and 2) have higher pI and considerably lower molecular weight than the wild-type BRCA1 protein. The molecular weight of protein 3 having one alteration (phenylalanine to leucine) varied slightly, and there was no difference in the characteristics of wild-type BRCA1 and protein 4. This study reveals the mutational spectrum of BRCA1 in patients with acute myeloid leukemia, representing unique missense and novel pathogenic mutations that can be further targeted for designing diagnostic and therapeutic strategies for acute myeloid leukemia.