A New Framework for the Use of Variant Interpretation Tools in Clinical Practice
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© 2023 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade
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Current ACMG/AMP guidelines for the use of sequence variants for genetic diagnosis
and treatment permit the use of in silico predictors as Supporting evidence (PP3 and
BP4 criteria). These criteria, however, lack quantitative support and leave clinicians and
scientists without standards for applying these criteria, leading to large interpretation
variability. To address this challenge, our team built upon previous work and introduced
a novel criterion that can be used to calibrate any computational model or any other
continuous-scale evidence on any variant type. We used it to estimate score intervals
corresponding to the four strengths of evidence for pathogenicity and benignity for
fourteen missense variant interpretation tools on a carefully assembled data sets of
known pathogenic and benign variants. We found that most tools achieved the Supporting
evidence level for both pathogenic and benign classification using newly established datadriven
thresholds. Importantly, at ...appropriate score thresholds, several in silico methods
can also provide Moderate and Strong evidence levels for a limited number of variants.
Based on these findings, we provided recommendations for quantitative revisions of the
PP3 and BP4 criteria within ACMG/AMP guidelines and the future assessment of in silico
methods for clinical interpretation.
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4th Belgrade Bioinformatics Conference, 2023, 4, 7-7Publisher:
- Belgrade : Institute of molecular genetics and genetic engineering
Note:
- Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 2023
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Radivojac, Predrag PY - 2023 UR - https://belbi.bg.ac.rs/ UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1942 AB - Current ACMG/AMP guidelines for the use of sequence variants for genetic diagnosis and treatment permit the use of in silico predictors as Supporting evidence (PP3 and BP4 criteria). These criteria, however, lack quantitative support and leave clinicians and scientists without standards for applying these criteria, leading to large interpretation variability. To address this challenge, our team built upon previous work and introduced a novel criterion that can be used to calibrate any computational model or any other continuous-scale evidence on any variant type. We used it to estimate score intervals corresponding to the four strengths of evidence for pathogenicity and benignity for fourteen missense variant interpretation tools on a carefully assembled data sets of known pathogenic and benign variants. We found that most tools achieved the Supporting evidence level for both pathogenic and benign classification using newly established datadriven thresholds. Importantly, at appropriate score thresholds, several in silico methods can also provide Moderate and Strong evidence levels for a limited number of variants. Based on these findings, we provided recommendations for quantitative revisions of the PP3 and BP4 criteria within ACMG/AMP guidelines and the future assessment of in silico methods for clinical interpretation. PB - Belgrade : Institute of molecular genetics and genetic engineering C3 - 4th Belgrade Bioinformatics Conference T1 - A New Framework for the Use of Variant Interpretation Tools in Clinical Practice EP - 7 SP - 7 VL - 4 UR - https://hdl.handle.net/21.15107/rcub_imagine_1942 ER -
@conference{ author = "Radivojac, Predrag", year = "2023", abstract = "Current ACMG/AMP guidelines for the use of sequence variants for genetic diagnosis and treatment permit the use of in silico predictors as Supporting evidence (PP3 and BP4 criteria). These criteria, however, lack quantitative support and leave clinicians and scientists without standards for applying these criteria, leading to large interpretation variability. To address this challenge, our team built upon previous work and introduced a novel criterion that can be used to calibrate any computational model or any other continuous-scale evidence on any variant type. We used it to estimate score intervals corresponding to the four strengths of evidence for pathogenicity and benignity for fourteen missense variant interpretation tools on a carefully assembled data sets of known pathogenic and benign variants. We found that most tools achieved the Supporting evidence level for both pathogenic and benign classification using newly established datadriven thresholds. Importantly, at appropriate score thresholds, several in silico methods can also provide Moderate and Strong evidence levels for a limited number of variants. Based on these findings, we provided recommendations for quantitative revisions of the PP3 and BP4 criteria within ACMG/AMP guidelines and the future assessment of in silico methods for clinical interpretation.", publisher = "Belgrade : Institute of molecular genetics and genetic engineering", journal = "4th Belgrade Bioinformatics Conference", title = "A New Framework for the Use of Variant Interpretation Tools in Clinical Practice", pages = "7-7", volume = "4", url = "https://hdl.handle.net/21.15107/rcub_imagine_1942" }
Radivojac, P.. (2023). A New Framework for the Use of Variant Interpretation Tools in Clinical Practice. in 4th Belgrade Bioinformatics Conference Belgrade : Institute of molecular genetics and genetic engineering., 4, 7-7. https://hdl.handle.net/21.15107/rcub_imagine_1942
Radivojac P. A New Framework for the Use of Variant Interpretation Tools in Clinical Practice. in 4th Belgrade Bioinformatics Conference. 2023;4:7-7. https://hdl.handle.net/21.15107/rcub_imagine_1942 .
Radivojac, Predrag, "A New Framework for the Use of Variant Interpretation Tools in Clinical Practice" in 4th Belgrade Bioinformatics Conference, 4 (2023):7-7, https://hdl.handle.net/21.15107/rcub_imagine_1942 .