Thomassen, Mads and Mesman, Romy L. S. and Hansen, Thomas V. O. and Menendez, Mireia and Rossing, Maria and Esteban-Sanchez, Ada and Tudini, Emma and Torngren, Therese and Parsons, Michael T. and Pedersen, Inge S. and Teo, Soo Hwang and Kruse, Torben A. and Moller, Pal and Borg, Ake and Jensen, Uffe B. and Christensen, Lise L. and Singer, Christian F. and Muhr, Daniela and Santamarina, Marta and Brandao, Rita and Andresen, Brage S. and Feng, Bing-Jian and Canson, Daffodil and Richardson, Marcy E. and Karam, Rachid and Pesaran, Tina and LaDuca, Holly and Conner, Blair R. and Abualkheir, Nelly and Hoang, Lily and Calleja, Fabienne M. G. R. and Andrews, Lesley and James, Paul A. and Bunyan, Dave and Hamblett, Amanda and Radice, Paolo and Goldgar, David E. and Walker, Logan C. and Engel, Christoph and Claes, Kathleen B. M. and Machackova, Eva and Baralle, Diana and Viel, Alessandra and Wappenschmidt, Barbara and Lazaro, Conxi and Vega, Ana and Vreeswijk, Maaike P. G. and de la Hoya, Miguel and Spurdle, Amanda B. (2022) Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach. HUMAN MUTATION, 43 (12). pp. 1921-1944. ISSN 1098-1004, DOI https://doi.org/10.1002/humu.24449.
Full text not available from this repository.Abstract
Skipping of BRCA2 exon 3 ( increment E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter increment 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. increment 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.
| Item Type: | Article |
|---|---|
| Funders: | Italian Ministry of Health; Den Norske Kreftforening, Spanish Health Research Foundation, NIHR Research Professorship, Ministry of Health of the Czech Republic MH CZ - DRO, Federal Ministry of Education & Research (BMBF) |
| Uncontrolled Keywords: | ACMG; AMP classification; BRCA2; dPCR; functional analysis; quantitation; splicing |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Medicine > Surgery Department |
| Depositing User: | Ms Koh Ai Peng |
| Date Deposited: | 31 Jul 2024 08:32 |
| Last Modified: | 31 Jul 2024 08:32 |
| URI: | http://eprints.um.edu.my/id/eprint/46227 |
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