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.

Miguel de la Hoya ; Omar Soukarieh ; Irene López-Perolio ; Ana Vega ; Logan C Walker ; Yvette van Ierland ; Diana Baralle ; Marta Santamariña ; Vanessa Lattimore ; Juul Wijnen ; +65 more... Philip Whiley ; Ana Blanco ; Michela Raponi ; Jan Hauke ; Barbara Wappenschmidt ; Alexandra Becker ; Thomas VO Hansen ; Raquel Behar ; KConFaB Investigators ; Diether Niederacher ; Norbert Arnold ; Bernd Dworniczak ; Doris Steinemann ; Ulrike Faust ; Wendy Rubinstein ; Peter J Hulick ; Claude Houdayer ; Sandrine M Caputo ; Laurent Castera ; Tina Pesaran ; Elizabeth Chao ; Carole Brewer ; Melissa C Southey ; Christi J van Asperen ; Christian F Singer ; Jan Sullivan ; Nicola Poplawski ; Phuong Mai ; Julian Peto ORCID logo ; Nichola Johnson ; Barbara Burwinkel ; Harald Surowy ; Stig E Bojesen ; Henrik Flyger ; Annika Lindblom ; Sara Margolin ; Jenny Chang-Claude ; Anja Rudolph ; Paolo Radice ; Laura Galastri ; Janet E Olson ; Emily Hallberg ; Graham G Giles ; Roger L Milne ; Irene L Andrulis ; Gord Glendon ; Per Hall ; Kamila Czene ; Fiona Blows ; Mitul Shah ; Qin Wang ; Joe Dennis ; Kyriaki Michailidou ; Lesley McGuffog ; Manjeet K Bolla ; Antonis C Antoniou ; Douglas F Easton ; Fergus J Couch ; Sean Tavtigian ; Maaike P Vreeswijk ; Michael Parsons ; Huong D Meeks ; Alexandra Martins ; David E Goldgar ; Amanda B Spurdle ; (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, 25 (11). pp. 2256-2268. ISSN 0964-6906 DOI: 10.1093/hmg/ddw094
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A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.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 pathogenic BRCA1 variant. 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 3.23 × 10-8 Our data indicate that c.594-2A > C is always in cis with 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 a per allele BRCA1 expression profile composed 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 that BRCA1c.[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 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.

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