Thomassen, Mads, Mesman, Romy L. S., Hansen, Thomas V. O., Menendez, Mireia, Rossing, Maria, Esteban-Sanchez, Ada ORCID: 0000-0002-1850-590X, Tudini, Emma ORCID: 0000-0002-5834-7862, Torngren, Therese, Parsons, Michael T., Pedersen, Inge S., Teo, Soo H., Kruse, Torben A., Moller, Pal, Borg, Ake, Jensen, Uffe B., Christensen, Lise L., Singer, Christian F., Muhr, Daniela, Santamarina, Marta, Brandao, Rita, Andresen, Brage S., Feng, Bing-Jian, Canson, Daffodil ORCID: 0000-0002-8104-822X, Richardson, Marcy E., Karam, Rachid, Pesaran, Tina, LaDuca, Holly, Conner, Blair R., Abualkheir, Nelly, Hoang, Lily, Calleja, Fabienne M. G. R., Andrews, Lesley, James, Paul A., Bunyan, Dave, Hamblett, Amanda, Radice, Paolo, Goldgar, David E., Walker, Logan C., Engel, Christoph ORCID: 0000-0002-7247-282X, Claes, Kathleen B. M., Machackova, Eva ORCID: 0000-0002-0246-1471, Baralle, Diana, Viel, Alessandra, Wappenschmidt, Barbara, Lazaro, Conxi, Vega, Ana, Vreeswijk, Maaike P. G., 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. Hum. Mutat., 43 (12). S. 1921 - 1945. LONDON: WILEY-HINDAWI. ISSN 1098-1004

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thomassen, MadsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mesman, Romy L. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Thomas V. O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menendez, MireiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossing, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esteban-Sanchez, AdaUNSPECIFIEDorcid.org/0000-0002-1850-590XUNSPECIFIED
Tudini, EmmaUNSPECIFIEDorcid.org/0000-0002-5834-7862UNSPECIFIED
Torngren, ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Inge S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Soo H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kruse, Torben A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, PalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borg, AkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jensen, Uffe B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christensen, Lise L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singer, Christian F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muhr, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santamarina, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandao, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andresen, Brage S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feng, Bing-JianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Canson, DaffodilUNSPECIFIEDorcid.org/0000-0002-8104-822XUNSPECIFIED
Richardson, Marcy E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karam, RachidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pesaran, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
LaDuca, HollyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conner, Blair R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abualkheir, NellyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoang, LilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calleja, Fabienne M. G. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrews, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
James, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bunyan, DaveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamblett, AmandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, Logan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Claes, Kathleen B. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Machackova, EvaUNSPECIFIEDorcid.org/0000-0002-0246-1471UNSPECIFIED
Baralle, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viel, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vreeswijk, Maaike P. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-698346
DOI: 10.1002/humu.24449
Journal or Publication Title: Hum. Mutat.
Volume: 43
Number: 12
Page Range: S. 1921 - 1945
Date: 2022
Publisher: WILEY-HINDAWI
Place of Publication: LONDON
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SEQUENCE VARIANTS; CANCER; CLASSIFICATION; GENE; MUTATIONS; RELEVANCE; BREAST; RISKMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69834

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