Abstract
Patients with a strong family history of breast cancer are often counseled to receive genetic screening for
BRCA1
and
BRCA2
mutations, the strongest known predictors of breast cancer. A major limitation of genetic testing is the number of inconclusive results due to unclassified
BRCA1
and
BRCA2
sequence variants. Many known deleterious
BRCA1
and
BRCA2
mutations affect splicing, and these typically lie near intron/exon boundaries. However, there are also potential internal exonic mutations that disrupt functional exonic splicing enhancer (ESE) sequences, resulting in exon skipping. Using previously established sequence matrices for the scoring of putative ESE motifs, we have systematically examined several
BRCA2
mutations for potential ESE disruption mutations. These predictions revealed that
BRCA2
T2722R (8393C→G), which segregates with affected individuals in a family with breast cancer, disrupts three potential ESE sites. Reverse-transcriptase polymerase chain reaction analysis confirms that this mutation causes exon skipping, leading to an out-of-frame fusion of
BRCA2
exons 17 and 19. This represents the first
BRCA2
missense mutation shown to be a predicted deleterious protein-truncating mutation and suggests a potentially useful method for determining the clinical significance of a subset of the many unclassified variants in
BRCA1
and
BRCA2
.