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Towards Increasing the Clinical Relevance of In Silico Methods to Predict Pathogenic Missense Variants

David L. Masica, Rachel Karchin, Ruth Nussinov
2016 PLoS Computational Biology  
The need to interpret these variants continues to motivate development of better in silico bioinformatic methods.  ...  Despite the development of dozens of such methods over the past 15 years, clinically relevant prediction accuracy remains elusive.  ...  enable development of new in silico bioinformatics methods to predict variant impact on endophenotypes.  ... 
doi:10.1371/journal.pcbi.1004725 pmid:27171182 pmcid:PMC4865359 fatcat:xdzpensdovdv3fvo3jjddg3opq

Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics

Corinna Ernst, Eric Hahnen, Christoph Engel, Michael Nothnagel, Jonas Weber, Rita K. Schmutzler, Jan Hauke
2018 BMC Medical Genomics  
Conclusion: We show that due to low specificities state-of-the-art in silico prediction tools are not suitable to predict pathogenicity of variants of uncertain significance in BRCA1/2.  ...  The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require interpretation.  ...  Acknowledgements The authors thank the German Cancer Aid (grant number 110837) for funding and Sandra Schmidt (Center for Familial Breast and Ovarian Cancer, Cologne) for excellent technical assistance  ... 
doi:10.1186/s12920-018-0353-y pmid:29580235 pmcid:PMC5870501 fatcat:ylcngnnmzrgqtde4p33qf3uqsm

Assessing performance of pathogenicity predictors using clinically-relevant variant datasets [article]

Adam C Gunning, Verity Fryer, James Fasham, Andrew H Crosby, Sian Ellard, Emma Baple, Caroline F Wright
2020 biorxiv/medrxiv   pre-print
Purpose: Pathogenicity predictors are an integral part of genomic variant interpretation but, despite their widespread usage, an independent validation of performance using a clinically-relevant dataset  ...  Results: Although the newer meta-predictors outperform the older tools, the performance of all pathogenicity predictors is substantially lower in the clinically-representative dataset.  ...  Acknowledgements We wish to thank all the patients and family members who participated in the study. We also thank Dr  ... 
doi:10.1101/2020.02.06.937169 fatcat:pmq2xqmsu5caha4wuantc3lvsa

Assessing performance of pathogenicity predictors using clinically relevant variant datasets

Adam C Gunning, Verity Fryer, James Fasham, Andrew H Crosby, Sian Ellard, Emma L Baple, Caroline F Wright
2020 Journal of Medical Genetics  
2.ResultsAlthough the newer meta-predictors outperform the older tools, the performance of all pathogenicity predictors is substantially lower in the clinically representative dataset.  ...  BackgroundPathogenicity predictors are integral to genomic variant interpretation but, despite their widespread usage, an independent validation of performance using a clinically relevant dataset has not  ...  Acknowledgements We wish to thank all the patients and family members who participated in the study.  ... 
doi:10.1136/jmedgenet-2020-107003 pmid:32843488 pmcid:PMC8327323 fatcat:p5arsgtt7janffoj2lgfl6almu

Using structural analysis to assess the impact of missense variants in MEN1 [article]

Richard C. Caswell, Martina M Owens, Adam C. Gunning, Sian Ellard, Caroline F. Wright
2019 bioRxiv   pre-print
variants with existing sequence- and conservation-based approaches can provide increased specificity in assessing the impact of missense variants in MEN1 in a clinical setting.  ...  ABSTRACTPurposeThermodynamic analysis of protein structure in silico has been shown to be effective in discriminating between the effects of benign and pathogenic variation in the MSH2 protein.  ...  For these reasons, methods to assist the classification of variants in MEN1 would be of clinical value.  ... 
doi:10.1101/661512 fatcat:r5n7ahlmpfab5leluyzscnsipu

Using structural analysis in silico to assess the impact of missense variants in MEN1

Richard C Caswell, Martina M Owens, Adam C Gunning, Sian Ellard, Caroline F Wright
2019 Journal of the Endocrine Society  
Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants.  ...  Subsequent analysis of 7 novel missense variants identified during clinical testing of MEN1 patients showed that all 7 were predicted to destabilise menin by >4 kcal/mol.  ...  subsequently used to calculate average values for each variant [38] .  ... 
doi:10.1210/js.2019-00260 pmid:31737856 pmcid:PMC6846327 fatcat:ohkpwnu2irh5heeyevcvdwqox4

Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

Bryony A. Thompson, Marc S. Greenblatt, Maxime P. Vallee, Johanna C. Herkert, Chloe Tessereau, Erin L. Young, Ivan A. Adzhubey, Biao Li, Russell Bell, Bingjian Feng, Sean D. Mooney, Predrag Radivojac (+9 others)
2012 Human Mutation  
The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions  ...  to estimate prior probabilities of pathogenicity for MMR gene missense substitutions.  ...  Acknowledgments For helpful discussions in refining the qualitative criteria that were used for qualitative classification of missense variants in this study, we thank the other members of the InSiGHT  ... 
doi:10.1002/humu.22214 pmid:22949387 pmcid:PMC4318556 fatcat:5m7wonq3tnbxdeabjnpzuq427m

Multimodal Analysis of SCN1A Missense Variants Improves Interpretation of Clinically Relevant Variants in Dravet Syndrome

Marina C. Gonsales, Maria Augusta Montenegro, Paula Preto, Marilisa M. Guerreiro, Ana Carolina Coan, Monica Paiva Quast, Benilton S. Carvalho, Iscia Lopes-Cendes
2019 Frontiers in Neurology  
Methods: We established a score classification workflow based on evidence of pathogenicity to adapt the classification of DS-related SCN1A missense variants.  ...  Objective: We aimed to improve the classification of SCN1A missense variants in patients with Dravet syndrome (DS) by combining and modifying the current variants classification criteria to minimize inconclusive  ...  ACKNOWLEDGMENTS We gratefully acknowledge the patients and their families for participating in this study.  ... 
doi:10.3389/fneur.2019.00289 pmid:31001185 pmcid:PMC6455056 fatcat:dfexqmqufnbrbaruhjdnlbfpwm

Enhanced prediction of gene and missense rare-variant pathogenicity by joint analysis of gene burden and amino-acid residue position [article]

Adam Waring, Andrew Harper, Silvia Salatino, Christopher Kramer, Stefan Neubauer, Kate Thomson, Hugh Watkins, Martin Farrall, HCMR Investigators
2019 bioRxiv   pre-print
Although rare missense variants underlying a number of Mendelian diseases have been noted to cluster in specific regions of proteins, this information may be underutilized when evaluating the pathogenicity  ...  In conclusion, the inclusion of amino-acid residue positional information enhances the accuracy of gene and rare variant pathogenicity interpretation.  ...  Acknowledgements We would like to acknowledge Anuj Goel for his bioinformatics support in data curation and Michael Bowman for his support in accessing data from the clinical genetics laboratory.  ... 
doi:10.1101/826164 fatcat:366d5vqkajdiditsqivyf5yhte

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

Marisa Encarnação, Maria Francisca Coutinho, Lisbeth Silva, Diogo Ribeiro, Souad Ouesleti, Teresa Campos, Helena Santos, Esmeralda Martins, Maria Teresa Cardoso, Laura Vilarinho, Sandra Alves
2020 International Journal of Molecular Sciences  
One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis.  ...  Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis.  ...  Acknowledgments: The authors are grateful to the patients, families and also to all colleagues who provided them valuable information. We also thank to the Facility of Sequencing, INSA.  ... 
doi:10.3390/ijms21176355 pmid:32883051 fatcat:2w5sqhchcfcjfihuo5dtfqjo4e

Dissecting in silico Mutation Prediction of Variants in African Genomes: Challenges and Perspectives

Christian Domilongo Bope, Emile R. Chimusa, Victoria Nembaware, Gaston K. Mazandu, Jantina de Vries, Ambroise Wonkam
2019 Frontiers in Genetics  
However, the variability in the in silico prediction methods and categorization of functionally relevant genetic variants can pose specific challenges in some populations.  ...  Genomic medicine is set to drastically improve clinical care globally due to high throughput technologies which enable speedy in silico detection and analysis of clinically relevant mutations.  ...  The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.  ... 
doi:10.3389/fgene.2019.00601 pmid:31293624 pmcid:PMC6603221 fatcat:53hsn6g5nvdn3jcaaw3revkzfm

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

Kristy Lee, Kate Krempely, Maegan E. Roberts, Michael J. Anderson, Fatima Carneiro, Elizabeth Chao, Katherine Dixon, Joana Figueiredo, Rajarshi Ghosh, David Huntsman, Pardeep Kaurah, Chimene Kesserwan (+16 others)
2018 Human Mutation  
framework to assess variant pathogenicity; however, these rules are not genespecific.  ...  Overall, the ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.  ...  of the Hereditary Cancer Clinical Domain Working Group for their experience and guidance in developing these rule specifications.  ... 
doi:10.1002/humu.23650 pmid:30311375 pmcid:PMC6188664 fatcat:atmxyuxg5nhi3bnzq2fwobfmla

A functional assay–based procedure to classify mismatch repair gene variants in Lynch syndrome

Mark Drost, Yvonne Tiersma, Bryony A. Thompson, Jane H. Frederiksen, Guido Keijzers, Dylan Glubb, Scott Kathe, Jan Osinga, Helga Westers, Lisa Pappas, Kenneth M. Boucher, Siska Molenkamp (+10 others)
2018 Genetics in Medicine  
To enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity  ...  Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data.  ...  Bayesian integration of cell-free in vitro MMR activity (CIMRA) assay values and in silico predictions of pathogenicity correctly classifies~90% of missense variants.  ... 
doi:10.1038/s41436-018-0372-2 pmid:30504929 pmcid:PMC7901556 fatcat:gl37kzkt4jbivjhs33s5svuecq

Pathogenicity Interpretation in the Age of Precision Medicine: The 2015 Annual Scientific Meeting of the Human Genome Variation Society

William S. Oetting, Steven E. Brenner, Anthony J. Brookes, Marc S. Greenblatt, Reece K. Hart, Rachel Karchin, Shamil R. Sunyaev, Peter E. Taschner
2016 Human Mutation  
The authors would like to thank the speakers for their help in the preparation of this report. This meeting was run in partnership with The Human Variome Project. Dr.  ...  Acknowledgments The Scientific Program Committee would like to thank Rania Horaitis, Heather Howard, and Timothy Smith for their professional help in running the HGVS Annual Meeting.  ...  In silico prediction of variant pathogenicity has the potential to be clinically important but there are weaknesses in the current paradigm.  ... 
doi:10.1002/humu.22958 pmid:26791113 pmcid:PMC4783187 fatcat:bybttx64drft5dqeeolelicu3m

Medical genomics: The intricate path from genetic variant identification to clinical interpretation

B. Quintáns, A. Ordóñez-Ugalde, P. Cacheiro, A. Carracedo, M.J. Sobrido
2014 Applied and Translational Genomics  
The field of medical genomics involves translating high throughput genetic methods to the clinic, in order to improve diagnostic efficiency and treatment decision making.  ...  There is no single piece of evidence enough on its own to make firm conclusions on the pathogenicity and disease causality of a given variant.  ...  Patricia Blanco for fruitful discussions on variant interpretation and clinical reporting, as well as to Dr. Jorge Amigo for bioinformatics support.  ... 
doi:10.1016/j.atg.2014.06.001 pmid:27284505 pmcid:PMC4887840 fatcat:d6s27q3aijh3tf34wpqkrfdfx4
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