Combined genetic and splicing analysis of BRCA1 c. 594-2A \ensuremath> C; 641A \ensuremath> G highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

Abstract

We confirm that BRCA1c.[594-2A \ensuremath> C;641A \ensuremath> G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.