Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression.

摘要: Germline mutations in the human breast cancer susceptibility genes BRCA1 and BRCA2 account for majority of hereditary ovarian cancer. In spite large number sequence variants identified mutation analyses, many these genetic alterations are still classified as unknown significance (VUS). this study, we evaluated 12 BRCA1/2 intronic order to differentiate their pathogenic or polymorphic effects on mRNA splicing process. We detected existence aberrant three (c.301-2delA/IVS6-2delA, c.441+1G>A/IVS7+1G>A, c.4986+6T>G/IVS16+6T>G) two (c.8487+1G>A/IVS19+1G>A c.8632-2A>G/IVS20-2A>G). All but one transcripts arise from affecting conserved splice acceptor donor sequences all would be predicted result expression truncated proteins. However, demonstrated that four splice-site (i.e., c.301-2delA, c.441+1G>A, c.4986+6T>G, c.8632-2A>G) with premature termination codons were highly unstable unlikely encode abundant a mutant protein. Three (c.212+3A>G/IVS5+3A>G, c.593+8A>G/IVS9+8A>G, c.4986-20A>G/IVS16-20A>G) (c.516-19C>T/IVS6-19C>T, c.7976-4_7976_3delTT/IVS17-4delTT, c.8487+19A>G/IVS19+19A>G, c.9256- 18C>A/IVS24- 18C>A) our studies show no normal process, they considered benign alterations. Our help clarify well provide information can used clinically counsel breast/ovarian prone families.