Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F22%3A00079084" target="_blank" >RIV/00209805:_____/22:00079084 - isvavai.cz</a>
Result on the web
<a href="https://onlinelibrary.wiley.com/doi/10.1002/humu.24449" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1002/humu.24449</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/humu.24449" target="_blank" >10.1002/humu.24449</a>
Alternative languages
Result language
angličtina
Original language name
Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30101 - Human genetics
Result continuities
Project
<a href="/en/project/NU20-03-00285" target="_blank" >NU20-03-00285: BIOINFORMATICS AND FUNCTIONAL ANALYSES OF SUSCEPTIBILITY VARIANTS SUPPORTING THE NGS-BASED TESTING OF HEREDITARY CANCERS IN THE CZECH REPUBLIC (II)</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Human mutation
ISSN
1059-7794
e-ISSN
1098-1004
Volume of the periodical
43
Issue of the periodical within the volume
12
Country of publishing house
US - UNITED STATES
Number of pages
24
Pages from-to
1921-1944
UT code for WoS article
000871206700001
EID of the result in the Scopus database
2-s2.0-85140357391