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Functional Impact of Missense Variants in BRCA1 Predicted by Supervised Learning

Rachel Karchin, Alvaro N. A. Monteiro, Sean V. Tavtigian, Marcelo A. Carvalho, Andrej Sali
2007 PLoS Computational Biology  
Citation: Karchin R, Monteiro ANA, Tavtigian SV, Carvalho MA, Sali A (2007) Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3(2): e26.  ...  Here we describe a supervised learning approach to classification of BRCA1 UCVs.  ...  The project has been supported by US National Institutes of Health grants F32 GM-072403-02, U01 GM-61390-04, R01 CA92309; the Sandler Family Supporting Foundation; an IBM SUR grant; and computer hardware  ... 
doi:10.1371/journal.pcbi.0030026 pmid:17305420 pmcid:PMC1797820 fatcat:p6ptmtdujrgmhmobd6s7yadbxu

Functional impact of missense variants in BRCA1 predicted by supervised learning

Rachel Karchin, Alvaro N.A. Monteiro, Sean V. Tavtigian, Marcelo A. Carvalho, Andrej Sali
2005 PLoS Computational Biology  
Citation: Karchin R, Monteiro ANA, Tavtigian SV, Carvalho MA, Sali A (2007) Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3(2): e26.  ...  Here we describe a supervised learning approach to classification of BRCA1 UCVs.  ...  The project has been supported by US National Institutes of Health grants F32 GM-072403-02, U01 GM-61390-04, R01 CA92309; the Sandler Family Supporting Foundation; an IBM SUR grant; and computer hardware  ... 
doi:10.1371/journal.pcbi.0030026.eor fatcat:ttoi4iypgvgf5gd4fue53i5ufa

Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML [article]

Steven N Hart, Eric C Polley, Hermela Shimelis, Siddhartha Yadav, Fergus J Couch
2019 bioRxiv   pre-print
In silico predictions of missense variants is an important consideration when interpreting variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes.  ...  We trained and evaluated hundreds of machine learning algorithms based on results from validated functional assays to better predict missense variants in these genes as damaging or neutral.  ...  Many in silico prediction models are derived from supervised learning methods using variants in many different genes across the genome.  ... 
doi:10.1101/792754 fatcat:unvown5h6bglbdjg2hpx5pfvga

Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1

Marcelo Carvalho, Maria A. Pino, Rachel Karchin, Jennifer Beddor, Martha Godinho-Netto, Rafael D. Mesquita, Renato S. Rodarte, Danielle C. Vaz, Viviane A. Monteiro, Siranoush Manoukian, Mara Colombo, Carla B. Ripamonti (+7 others)
2009 Mutation research  
We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models.  ...  The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Δ exons 16/17) in the mRNA  ...  Structural analysis Prediction of the impact of amino acid changes in the BRCT domains was obtained by previously described bioinformatics supervised learning computation models [18, [25] [26] [27] .  ... 
doi:10.1016/j.mrfmmm.2008.09.017 pmid:18992264 pmcid:PMC2682550 fatcat:xosspn4uwvekzowg5bidt7rjjm

Predicting Pathogenicity of Missense Variants with Weakly Supervised Regression [article]

Yue Cao, Yuanfei Sun, Mostafa Karimi, Haoran Chen, Oluwaseyi Moronfoye, Yang Shen
2019 bioRxiv   pre-print
On the platform enabled by CAGI (Critical Assessment of Genome Interpretation), we develop a novel "weakly supervised" regression (WSR) model that not only predicts precise clinical significance (probability  ...  WSR model interpretation and protein structural interpretation reach consensus in corroborating the most probable molecular mechanisms by which some pathogenic BRCA1 variants confer clinical significance  ...  approach the task with supervised learning, we collected missense variants data similarly classified using the five-tier clinical significance system and publicly available in the ClinVar database (Landrum  ... 
doi:10.1101/545913 fatcat:b3hcztp4nragxevj2ceh6mgssu

Analysis of BRCA gene missense mutations

Stella W.S. Lai, Rebecca M. Lopes, Elaine Doherty, Debra O. Prosser, Rongying Tang, Donald R. Love
2015 Journal of Biomedical Engineering and Informatics  
The interpretation of VUSs has been challenging due to the discordance of prediction results and their classification in different locus-specific databases (LSDBs).  ...  With the significant progress in sequencing technologies over the last 10 years, a concomitant increase in the detection of variants of uncertain significance (VUSs) has been reported with an increasing  ...  This tool compiles and displays all the functional data for all documented variants in the BRCA1 gene, which allows direct comparisons between functional data and strengthens the classification system  ... 
doi:10.5430/jbei.v2n1p91 fatcat:e5ouxxyv6jfstgsf63iyrzy3dm

Predicting functional effect of missense variants using graph attention neural networks [article]

Haicang Zhang, Michelle S Xu, Wendy K Chung, Yufeng Shen
2021 bioRxiv   pre-print
Finally, the model supports transfer learning to optimize gain- and loss-of-function predictions in sodium and calcium channels.  ...  Evaluated by deep mutational scan data, gMVP outperforms published methods in identifying damaging variants in TP53, PTEN, BRCA1, and MSH2.  ...  Acknowledgements This work was supported by NIH grants R01GM120609, R03HL147197, and U01HG008680. We thank Dr. Xiao Fan, Yige Zhao, Guojie Zhong, Dr. Mohammed AlQuraishi, and Dr.  ... 
doi:10.1101/2021.04.22.441037 fatcat:k6ritpllxbbm7llhyr7ossd64e

Clinical Classification ofBRCA1DNA Missense Variants: H1686Q Is a Novel Pathogenic Mutation Occurring in the Ontogenetically Invariant THV Motif of the N-Terminal BRCT Domain

Giuseppe Giannini, Carlo Capalbo, Laura Ottini, Amelia Buffone, Laura De Marchis, Elena Margaria, Domenico Vitolo, Enrico Ricevuto, Christian Rinaldi, Massimo Zani, Sergio Ferraro, Paolo Marchetti (+4 others)
2008 Journal of Clinical Oncology  
Karchin R, Monteiro AN, Tavtigian SV, et al: Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3:e26 2007 20.  ...  Analysis of the impact of the H1686Q substitution on BRCAI protein function performed by the PolyPhen software (http://genetics.bwh.harvard .edu/pph/) predicted that the mutation is probably damaging with  ... 
doi:10.1200/jco.2008.18.2089 pmid:18757339 fatcat:7rnlw52oizc5bfaggtnjne7g6y

In Reply

Marco Montagna, Sandro Malacrida
2008 Journal of Clinical Oncology  
Karchin R, Monteiro AN, Tavtigian SV, et al: Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3:e26 2007 20.  ...  Glover JN, Williams RS, Lee MS: Interacti phosphoproteins: Tangled up in two nd 3. Karchin R, Monteiro AN, Tavtigian SV, tior 5 variants in BRCA1 predicted by supervised learning.  ... 
doi:10.1200/jco.2008.18.2667 fatcat:nopqb4lcmrdvlfuxwycbp2vjza

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios

Rachel Karchin, Mukesh Agarwal, Andrej Sali, Fergus Couch, Mary S Beattie
2008 Cancer Informatics  
We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function.  ...  Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1) interpreting the medical relevance of predictive scores is difficult  ...  The content is solely the responsibility of the authors and does not necessarily represent the offi cial view of the NCRR or the National Institutes of Health.  ... 
pmid:19043619 pmcid:PMC2587343 fatcat:slvl7vcvbrf47itel4e6kwj42a

In silico analysis of missense substitutions using sequence-alignment based methods

Sean V. Tavtigian, Marc S. Greenblatt, Fabienne Lesueur, Graham B. Byrnes
2008 Human Mutation  
In this paper, we review and/or make suggestions with respect to 1) the rationale for using in silico methods to help predict the consequences of missense variants, 2) important aspects of creating PMSAs  ...  ) of the gene of interest for almost any missense sequence variant, and 2) for many variants, structural features of wild type and variant proteins.  ...  Acknowledgments This work was supported by grants from the National Institutes of Health (CA 96536, MSG) and the Lake Champlain Cancer Research Organization (MSG).  ... 
doi:10.1002/humu.20892 pmid:18951440 pmcid:PMC3431198 fatcat:3lta2476pbcofmgfhamdnpf37q

Variant effect prediction tools assessed using independent, functional assay-based datasets: implications for discovery and diagnostics

Khalid Mahmood, Chol-hee Jung, Gayle Philip, Peter Georgeson, Jessica Chung, Bernard J. Pope, Daniel J. Park
2017 Human Genomics  
Contemporary variant effect prediction tools are unlikely to be as accurate at the general prediction of functional impacts on proteins as reported prior.  ...  Genetic variant effect prediction algorithms are used extensively in clinical genomics and research to determine the likely consequences of amino acid substitutions on protein function.  ...  Acknowledgements This work was supported by Melbourne Bioinformatics through Resource Allocation VR0002.  ... 
doi:10.1186/s40246-017-0104-8 pmid:28511696 pmcid:PMC5433009 fatcat:2fyw2qxmdjdcljt2tiji7eczoq

Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant

Jun Li, Ping Wang, Cuiyun Zhang, Sile Han, Han Xiao, Zhiyuan Liu, Xiaoyan Wang, Weiling Liu, Bing Wei, Jie Ma, Hongle Li, Yongjun Guo
2022 Frontiers in Oncology  
By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict  ...  Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients' family histories.  ...  Most VUSs in BRCA1/2 are missense variants, which have uncertain influences on the function of the protein product and the cancer risk of the carrier in question.  ... 
doi:10.3389/fonc.2021.812656 pmid:35087763 pmcid:PMC8789006 fatcat:zmaplxqsrberbpo6aevqa5wz24

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Wejdan M. Alenezi, Caitlin T. Fierheller, Neil Recio, Patricia N. Tonin
2020 Genes  
Soon after the discovery of BRCA1 and BRCA2 over 20 years ago, it became apparent that not all hereditary breast and/or ovarian cancer syndrome families were explained by germline variants in these cancer  ...  biological assays of BARD1 variants to assess their effect on protein function; and (iii) association studies of BARD1 variants in family-based and case-control study groups to assess cancer risk.  ...  The authors acknowledge the National Comprehensive Cancer Network guidelines for information regarding clinical management of carriers of variants in cancer predisposing genes.  ... 
doi:10.3390/genes11080856 pmid:32726901 fatcat:euxfw6xw35fp5bsrftjgk5r33m

Using deep mutational scanning data to benchmark computational phenotype predictors and identify pathogenic missense mutations [article]

Benjamin J. Livesey, Joseph A. Marsh
2019 bioRxiv   pre-print
We also evaluate the ability of DMS measurements and computational phenotype predictors to discriminate between pathogenic and benign missense variants.  ...  AbstractIn order to deal with the huge number of novel protein-coding variants being identified by genome and exome sequencing studies, many computational phenotype predictors have been developed.  ...  BL is supported by the MRC Precision Medicine Doctoral Training Programme.  ... 
doi:10.1101/855957 fatcat:e32bscszb5czdmajtgfm3yl5my
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