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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

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • 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