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

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Standard

Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach. / Thomassen, Mads; Mesman, Romy L. S.; Hansen, Thomas V. O.; Menendez, Mireia; Rossing, Maria; Esteban-Sánchez, Ada; Tudini, Emma; Törngren, Therese; Parsons, Michael T.; Pedersen, Inge S.; Teo, Soo H.; Kruse, Torben A.; Møller, Pål; Borg, Åke; Jensen, Uffe B.; Christensen, Lise L.; Singer, Christian F.; Muhr, Daniela; Santamarina, Marta; Brandao, Rita; Andresen, Brage S.; Feng, Bing-Jian; Canson, Daffodil; Richardson, Marcy E.; Karam, Rachid; Pesaran, Tina; LaDuca, Holly; Conner, Blair R.; Abualkheir, Nelly; Hoang, Lily; Calléja, Fabienne M G R; Andrews, Lesley; James, Paul A.; Bunyan, Dave; Hamblett, Amanda; Radice, Paolo; Goldgar, David E.; Walker, Logan C.; Engel, Christoph; Claes, Kathleen B. M.; Macháčková, Eva; Baralle, Diana; Viel, Alessandra; Wappenschmidt, Barbara; Lazaro, Conxi; Vega, Ana; Vreeswijk, Maaike P G; de la Hoya, Miguel; Spurdle, Amanda B.; ENIGMA Consortium.

I: Human Mutation, Bind 43, Nr. 12, 2022, s. 1921-1944.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Thomassen, M, Mesman, RLS, Hansen, TVO, Menendez, M, Rossing, M, Esteban-Sánchez, A, Tudini, E, Törngren, T, Parsons, MT, Pedersen, IS, Teo, SH, Kruse, TA, Møller, P, Borg, Å, Jensen, UB, Christensen, LL, Singer, CF, Muhr, D, Santamarina, M, Brandao, R, Andresen, BS, Feng, B-J, Canson, D, Richardson, ME, Karam, R, Pesaran, T, LaDuca, H, Conner, BR, Abualkheir, N, Hoang, L, Calléja, FMGR, Andrews, L, James, PA, Bunyan, D, Hamblett, A, Radice, P, Goldgar, DE, Walker, LC, Engel, C, Claes, KBM, Macháčková, E, Baralle, D, Viel, A, Wappenschmidt, B, Lazaro, C, Vega, A, Vreeswijk, MPG, de la Hoya, M, Spurdle, AB & ENIGMA Consortium 2022, 'Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach', Human Mutation, bind 43, nr. 12, s. 1921-1944. https://doi.org/10.1002/humu.24449

APA

Thomassen, M., Mesman, R. L. S., Hansen, T. V. O., Menendez, M., Rossing, M., Esteban-Sánchez, A., Tudini, E., Törngren, T., Parsons, M. T., Pedersen, I. S., Teo, S. H., Kruse, T. A., Møller, P., Borg, Å., Jensen, U. B., Christensen, L. L., Singer, C. F., Muhr, D., Santamarina, M., ... ENIGMA Consortium (2022). Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach. Human Mutation, 43(12), 1921-1944. https://doi.org/10.1002/humu.24449

Vancouver

Thomassen M, Mesman RLS, Hansen TVO, Menendez M, Rossing M, Esteban-Sánchez A o.a. Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach. Human Mutation. 2022;43(12):1921-1944. https://doi.org/10.1002/humu.24449

Author

Thomassen, Mads ; Mesman, Romy L. S. ; Hansen, Thomas V. O. ; Menendez, Mireia ; Rossing, Maria ; Esteban-Sánchez, Ada ; Tudini, Emma ; Törngren, Therese ; Parsons, Michael T. ; Pedersen, Inge S. ; Teo, Soo H. ; Kruse, Torben A. ; Møller, Pål ; Borg, Åke ; Jensen, Uffe B. ; Christensen, Lise L. ; Singer, Christian F. ; Muhr, Daniela ; Santamarina, Marta ; Brandao, Rita ; Andresen, Brage S. ; Feng, Bing-Jian ; Canson, Daffodil ; Richardson, Marcy E. ; Karam, Rachid ; Pesaran, Tina ; LaDuca, Holly ; Conner, Blair R. ; Abualkheir, Nelly ; Hoang, Lily ; Calléja, Fabienne M G R ; Andrews, Lesley ; James, Paul A. ; Bunyan, Dave ; Hamblett, Amanda ; Radice, Paolo ; Goldgar, David E. ; Walker, Logan C. ; Engel, Christoph ; Claes, Kathleen B. M. ; Macháčková, Eva ; Baralle, Diana ; Viel, Alessandra ; Wappenschmidt, Barbara ; Lazaro, Conxi ; Vega, Ana ; Vreeswijk, Maaike P G ; de la Hoya, Miguel ; Spurdle, Amanda B. ; ENIGMA Consortium. / Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach. I: Human Mutation. 2022 ; Bind 43, Nr. 12. s. 1921-1944.

Bibtex

@article{b524ea37c8ed48609f69c91fe616d50c,
title = "Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach",
abstract = "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.",
keywords = "ACMG/AMP classification, BRCA2, dPCR, functional analysis, quantitation, splicing",
author = "Mads Thomassen and Mesman, {Romy L. S.} and Hansen, {Thomas V. O.} and Mireia Menendez and Maria Rossing and Ada Esteban-S{\'a}nchez and Emma Tudini and Therese T{\"o}rngren and Parsons, {Michael T.} and Pedersen, {Inge S.} and Teo, {Soo H.} and Kruse, {Torben A.} and P{\aa}l M{\o}ller and {\AA}ke Borg and Jensen, {Uffe B.} and Christensen, {Lise L.} and Singer, {Christian F.} and Daniela Muhr and Marta Santamarina and Rita Brandao and Andresen, {Brage S.} and Bing-Jian Feng and Daffodil Canson and Richardson, {Marcy E.} and Rachid Karam and Tina Pesaran and Holly LaDuca and Conner, {Blair R.} and Nelly Abualkheir and Lily Hoang and Call{\'e}ja, {Fabienne M G R} and Lesley Andrews and James, {Paul A.} and Dave Bunyan and Amanda Hamblett and Paolo Radice and Goldgar, {David E.} and Walker, {Logan C.} and Christoph Engel and Claes, {Kathleen B. M.} and Eva Mach{\'a}{\v c}kov{\'a} and Diana Baralle and Alessandra Viel and Barbara Wappenschmidt and Conxi Lazaro and Ana Vega and Vreeswijk, {Maaike P G} and {de la Hoya}, Miguel and Spurdle, {Amanda B.} and {ENIGMA Consortium}",
note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.",
year = "2022",
doi = "10.1002/humu.24449",
language = "English",
volume = "43",
pages = "1921--1944",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "JohnWiley & Sons, Inc.",
number = "12",

}

RIS

TY - JOUR

T1 - Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants

T2 - Application of a points-based ACMG/AMP approach

AU - Thomassen, Mads

AU - Mesman, Romy L. S.

AU - Hansen, Thomas V. O.

AU - Menendez, Mireia

AU - Rossing, Maria

AU - Esteban-Sánchez, Ada

AU - Tudini, Emma

AU - Törngren, Therese

AU - Parsons, Michael T.

AU - Pedersen, Inge S.

AU - Teo, Soo H.

AU - Kruse, Torben A.

AU - Møller, Pål

AU - Borg, Åke

AU - Jensen, Uffe B.

AU - Christensen, Lise L.

AU - Singer, Christian F.

AU - Muhr, Daniela

AU - Santamarina, Marta

AU - Brandao, Rita

AU - Andresen, Brage S.

AU - Feng, Bing-Jian

AU - Canson, Daffodil

AU - Richardson, Marcy E.

AU - Karam, Rachid

AU - Pesaran, Tina

AU - LaDuca, Holly

AU - Conner, Blair R.

AU - Abualkheir, Nelly

AU - Hoang, Lily

AU - Calléja, Fabienne M G R

AU - Andrews, Lesley

AU - James, Paul A.

AU - Bunyan, Dave

AU - Hamblett, Amanda

AU - Radice, Paolo

AU - Goldgar, David E.

AU - Walker, Logan C.

AU - Engel, Christoph

AU - Claes, Kathleen B. M.

AU - Macháčková, Eva

AU - Baralle, Diana

AU - Viel, Alessandra

AU - Wappenschmidt, Barbara

AU - Lazaro, Conxi

AU - Vega, Ana

AU - Vreeswijk, Maaike P G

AU - de la Hoya, Miguel

AU - Spurdle, Amanda B.

AU - ENIGMA Consortium

N1 - Publisher Copyright: © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - ACMG/AMP classification

KW - BRCA2

KW - dPCR

KW - functional analysis

KW - quantitation

KW - splicing

U2 - 10.1002/humu.24449

DO - 10.1002/humu.24449

M3 - Journal article

C2 - 35979650

AN - SCOPUS:85140357391

VL - 43

SP - 1921

EP - 1944

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 12

ER -

ID: 329441049