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Åke Borg

Åke Borg

Principal investigator

Åke Borg

Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach


  • Mads Thomassen
  • Romy L.S. Mesman
  • Thomas V.O. Hansen
  • Mireia Menendez
  • Maria Rossing
  • Ada Esteban-Sánchez
  • Emma Tudini
  • Therese Törngren
  • Michael T. Parsons
  • Inge S. Pedersen
  • Soo H. Teo
  • Torben A. Kruse
  • Pål Møller
  • Åke Borg
  • Uffe B. Jensen
  • Lise L. Christensen
  • Christian F. Singer
  • Daniela Muhr
  • Marta Santamarina
  • Rita Brandao
  • Brage S. Andresen
  • Bing Jian Feng
  • Daffodil Canson
  • Marcy E. Richardson
  • Rachid Karam
  • Tina Pesaran
  • Holly LaDuca
  • Blair R. Conner
  • Nelly Abualkheir
  • Lily Hoang
  • Fabienne M.G.R. Calléja
  • Lesley Andrews
  • Paul A. James
  • Dave Bunyan
  • Amanda Hamblett
  • Paolo Radice
  • David E. Goldgar
  • Logan C. Walker
  • Christoph Engel
  • Kathleen B.M. Claes
  • Eva Macháčková
  • Diana Baralle
  • Alessandra Viel
  • Barbara Wappenschmidt
  • Conxi Lazaro
  • Ana Vega
  • Maaike P.G. Vreeswijk
  • Miguel de la Hoya
  • Amanda B. Spurdle

Summary, in English

Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.


  • LUCC: Lund University Cancer Centre
  • Familial Breast Cancer
  • Breastcancer-genetics

Publishing year







Human Mutation





Document type

Journal article


John Wiley & Sons Inc.


  • Medical Genetics


  • ACMG/AMP classification
  • BRCA2
  • dPCR
  • functional analysis
  • quantitation
  • splicing



Research group

  • Familial Breast Cancer


  • ISSN: 1059-7794