Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.
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de la Hoya, M.
Walker, L. C.
van Ierland, Y.
Wijnen, J. T.
Human molecular genetics
Archived with thanks to Human molecular genetics
A recent analysis using family history weighting and co-observation classification modeling indicated thatBRCA1c.594-2A>C (IVS9-2A>C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenicBRCA1variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A>C. The combined odds for causality considering case-control, segregation, and breast tumor pathology information was 3.23x10(-8) Our data indicate that c.594-2A>C is always inciswith c.641A>G.The spliceogenic effect of c.[594-2A>C;641A>G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A>C; 641A>G] caused exon 10 skipping, albeit not due to c.594-2A>C impairing the acceptor site but rather by c.641A>G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with aper allele BRCA1expression profile comprised of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm thatBRCA1c.[594-2A>C;641A>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 inBRCA1exons 9 or 10, or any otherBRCA1allele 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.
Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. 2016 Jun 1;25(11):2256-2268