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

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Clinical genetic testing for BRCA1 and BRCA2 mutations is crucial for assessing hereditary breast and ovarian cancer (HBOC) risk.
• Classifying the functional impact of rare, non-truncating variants in these genes presents a significant challenge in genetic diagnostics.

Observation:

• A specific BRCA1 missense mutation, 331G > A (c.212G>A, p.Arg71Lys or R71K), was identified at the last nucleotide of exon 5.
• cDNA analysis revealed that the R71K mutation promotes aberrant splicing, resulting in a transcript with a 22-base pair deletion in exon 5.
• This splicing defect leads to the production of a severely truncated BRCA1 protein (63 amino acids) and completely abolishes normal transcript generation from the mutant allele.

Findings:

• The BRCA1 R71K mutation completely abrogates normal splicing, preventing the production of functional BRCA1 protein.
• Loss of heterozygosity analysis in a tumor specimen further supports the pathogenic role of this variant.

Implications:

• The BRCA1 331G > A (R71K) substitution is confirmed as a deleterious mutation, directly contributing to cancer predisposition.
• Accurate classification of such variants is essential for precise genetic counseling and clinical management of hereditary cancer syndromes.