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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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  • 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
  • Philip Whiley
  • Ana Blanco
  • Michela Raponi
  • Jan Hauke
  • Barbara Wappenschmidt
  • Alexandra Becker
  • Thomas V O 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
  • 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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind25
Udgave nummer11
Sider (fra-til)2256-2268
Antal sider13
ISSN0964-6906
DOI
StatusUdgivet - 1 jun. 2016

ID: 49434068