BRCA1 R71K missense mutation contributes to cancer predisposition by increasing alternative transcript levels

Abstract

Mutation screening of the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare non-truncating sequence variants in the BRCA1 and BRCA2 genes is problematic because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. The BRCA1 331G > A substitution mutation, which occurs at the last nucleotide of exon 5, results in an Arg-to-Lys change at codon 71 (R71K). cDNA analysis indicated that the R71K mutation significantly increases the level of a transcript, characterized by a 22 bp deletion in exon 5, which putatively produces a truncated BRCA1 protein of 63 amino acids. The mutation completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Analysis of a tumor specimen indicates loss of heterozygosity. These results support the conclusion that BRCA1 331G > A (R71K) is a deleterious mutation.

Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants

“…[Friedman et al., , ; Gayther et al., ; Petrij‐Bosch et al., ; Xu et al., ; Hoffman et al., ; Mazoyer et al., ; Fetzer et al., ; Ozcelik et al., ; Pyne et al., ; Santarosa et al., ; Scholl et al., ; Hartikainen et al., ; Pyne et al., ; Laskie Ostrow et al., ; Vega et al., ; Claes et al., ; Fackenthal et al., ; Howlett et al., ; Krajc et al., ; Meindl, ; Agata et al., ; Claes et al., ; Campos et al., ; Hofmann et al., ; Keaton et al., ; Yang et al., ; Brose et al., ; Sharp et al., ; Tesoriero et al., ; Bonatti et al., ; Chen et al., ; Chenevix‐Trench et al., ; Beristain et al., ; Ang et al., ; Anczukow et al., ; Bonnet et al., ; Farrugia et al., ; Goina et al., ; Kwong et al., ; Machackova et al., ; Spearman et al., ; Caux‐Moncoutier et al., ; Gutierrez‐Enriquez et al., ; Li et al., ; Vreeswijk et al., ; Willems et al., ; Dosil et al., ; Gaildrat et al., ; Hansen et al., ; Rouleau et al., ; Sanz et al., ; Steffensen et al., ; Walker et al., ; Whiley et al., ; Brandao et al., ; Thery et al., ; Whiley et al., ; Zhang et al., ; Acedo et al., ; Gaildrat et al., ; Houdayer et al., ; Joose et al. ; Menendez et al.,…”

Comparative In Vitro and In Silico Analyses of Variants in Splicing Regions of BRCA1 and BRCA2 Genes and Characterization of Novel Pathogenic Mutations

“…Spliceogenic mutations of group B included 6 already analyzed ( BRCA1 c.212G>A, c.213−11T>G, and c.4484G>T, and BRCA2 c.631G>A, c.8754+3G>C, and c.9117G>A) [11], [18], [19], [21], [22], [26], [44]–[50] and 2 newly characterized (c.134+3_134+6delAAGT, c.4986+5G>A in BRCA1 ). Three mutations caused the skipping of an entire exon: BRCA1 c.4484G>T (exon 14) (Fig.…”

GT198 Splice Variants Display Dominant-Negative Activities and Are Induced by Inactivating Mutations

“…12 Consistently, germline mutations in BRCA1 exon 11 promote the expression of BRCA1Δ11b. 13 Additional germline mutations in BRCA1 have also been identified, causing aberrant splicing 14,15 or altering alternative splicing. [16][17][18] Since a single pre-mRNA can be processed to generate multiple functional isoforms, it is essential to analyze the interrelationship between wildtype and splice variants when characterizing gene functions in cancer or disease.…”