Mar 24, 2020

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23-a likely pathogenic variant with reduced penetrance?

European Journal of Human Genetics : EJHG
Hildegunn Høberg-VettiPer Morten Knappskog

Abstract

Rare sequence variants in the non-coding part of the BRCA genes are often reported as variants of uncertain significance (VUS), which leave patients and doctors in a challenging position. The aim of this study was to determine the pathogenicity of the BRCA1 c.5407-25T>A variant found in 20 families from Norway, France and United States with suspected hereditary breast and ovarian cancer. This was done by combining clinical and family information with allele frequency data, and assessment of the variant's effect on mRNA splicing. Mean age at breast (n = 12) and ovarian (n = 11) cancer diagnosis in female carriers was 49.9 and 60.4 years, respectively. The mean Manchester score in the 20 families was 16.4. The allele frequency of BRCA1 c.5407-25T>A was 1/64,566 in non-Finnish Europeans (gnomAD database v2.1.1). We found the variant in 1/400 anonymous Norwegian blood donors and 0/784 in-house exomes. Sequencing of patient-derived cDNA from blood, normal breast and ovarian tissue showed that BRCA1 c.5407-25T>A leads to skipping of exon 23, resulting in frameshift and protein truncation: p.(Gly1803GlnfsTer11). Western blot analysis of transiently expressed BRCA1 proteins in HeLa cells showed a reduced amount of the truncated protein...Continue Reading

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Mentioned in this Paper

DNA, Complementary
Gene Mutant
Exome
Genetic Carriers
Exons
HeLa Cells
BRCA1 Gene Mutation
Blood
BRCA1 Protein
RNA, Messenger, Splicing

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