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.


de la Hoya, M; Soukarieh, O; López-Perolio, I; Vega, A; Walker, LC; van Ierland, Y; Baralle, D; Santamariña, M; Lattimore, V; Wijnen, J; Whiley, P; Blanco, A; Raponi, M; Hauke, J; Wappenschmidt, B; Becker, A; Hansen, TV; Behar, R; KConFaB investigators; Niederacher, D; Arnold, N; Dworniczak, B; Steinemann, D; Faust, U; Rubinstein, W; Hulick, PJ; Houdayer, C; Caputo, SM; Castera, L; Pesaran, T; Chao, E; Brewer, C; Southey, MC; van Asperen, CJ; Singer, CF; Sullivan, J; Poplawski, N; Mai, P; Peto, J; Johnson, N; Burwinkel, B; Surowy, H; Bojesen, SE; Flyger, H; Lindblom, A; Margolin, S; Chang-Claude, J; Rudolph, A; Radice, P; Galastri, L; Olson, JE; Hallberg, E; Giles, GG; Milne, RL; Andrulis, IL; Glendon, G; Hall, P; Czene, K; Blows, F; Shah, M; Wang, Q; Dennis, J; Michailidou, K; McGuffog, L; Bolla, MK; Antoniou, AC; Easton, DF; Couch, FJ; Tavtigian, S; Vreeswijk, M; Parsons, M; Meeks, H; Martins, A; Goldgar, DE; Spurdle, AB; (2016) 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. Human molecular genetics. ISSN 0964-6906 DOI: 10.1093/hmg/ddw094

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Abstract

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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Research Centre: Vaccine Centre
PubMed ID: 27008870
URI: http://researchonline.lshtm.ac.uk/id/eprint/2535704

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