Leveraging cancer mutation data to inform the pathogenicity classification of germline missense variants DOI Creative Commons
Bushra Haque, David Cheerie, Amy Pan

и другие.

PLoS Genetics, Год журнала: 2025, Номер 21(1), С. e1011540 - e1011540

Опубликована: Янв. 6, 2025

Innovative and easy-to-implement strategies are needed to improve the pathogenicity assessment of rare germline missense variants. Somatic cancer driver mutations identified through large-scale tumor sequencing studies often impact genes that also associated with Mendelian disorders. The use mutation data aid in interpretation variants, regardless whether gene is a hereditary predisposition syndrome or non-cancer-related developmental disorder, has not been systematically assessed. We extracted putative from Cancer Hotspots database annotated them as including presence/absence classification ClinVar. trained two supervised learning models (logistic regression random forest) predict variant classifications variants ClinVar using Hotspot (training dataset). performance each model was evaluated an independent test dataset generated part searching public private genome-wide datasets ~1.5 million individuals. Of 2,447 mutations, 691 corresponding had previously classified ClinVar: 426 (61.6%) likely pathogenic/pathogenic, 261 (37.8%) uncertain significance, 4 (0.6%) benign/benign. odds ratio for pathogenic/pathogenic 28.3 (95% confidence interval: 24.2–33.1, p < 0.001), compared all other same 216 genes. Both showed high correlation assessments training dataset. There area under precision-recall curve values (0.847 0.829) receiver-operating characteristic (0.821 0.774) logistic forest models, respectively, when applied With techniques, our study shows can be leveraged variation potentially causing

Язык: Английский

Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup DOI Creative Commons
Logan C. Walker, Miguel de la Hoya, George A. R. Wiggins

и другие.

The American Journal of Human Genetics, Год журнала: 2023, Номер 110(7), С. 1046 - 1067

Опубликована: Июнь 22, 2023

Язык: Английский

Процитировано

122
ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction DOI Creative Commons
Pascal Notin, Aaron W. Kollasch, Daniel P. Ritter

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 8, 2023

Predicting the effects of mutations in proteins is critical to many applications, from understanding genetic disease designing novel that can address our most pressing challenges climate, agriculture and healthcare. Despite a surge machine learning-based protein models tackle these questions, an assessment their respective benefits challenging due use distinct, often contrived, experimental datasets, variable performance across different families. Addressing requires scale. To end we introduce ProteinGym, large-scale holistic set benchmarks specifically designed for fitness prediction design. It encompasses both broad collection over 250 standardized deep mutational scanning assays, spanning millions mutated sequences, as well curated clinical datasets providing high-quality expert annotations about mutation effects. We devise robust evaluation framework combines metrics design, factors known limitations underlying methods, covers zero-shot supervised settings. report diverse 70 high-performing various subfields (eg., alignment-based, inverse folding) into unified benchmark suite. open source corresponding codebase, MSAs, structures, model predictions develop user-friendly website facilitates data access analysis.

Язык: Английский

Процитировано

90
Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing DOI Creative Commons
Elaine Chen, Flavia M. Facio,

Kerry Aradhya

и другие.

JAMA Network Open, Год журнала: 2023, Номер 6(10), С. e2339571 - e2339571

Опубликована: Окт. 25, 2023

Variants of uncertain significance (VUSs) are rampant in clinical genetic testing, frustrating clinicians, patients, and laboratories because the uncertainty hinders diagnoses management. A comprehensive assessment VUSs across many disease genes is needed to guide efforts reduce uncertainty.To describe sources, gene distribution, population-level attributes evaluate impact different types evidence used reclassify them.This cohort study germline DNA variant data from individuals referred by clinicians for diagnostic testing hereditary disorders. Participants included whom panel was conducted between September 9, 2014, 7, 2022. Data were analyzed 1, 2022, April 2023.The outcomes interest VUS rates (stratified age; clinician-reported race, ethnicity, ancestry groups; panels; attributes), percentage reclassified as benign or likely vs pathogenic pathogenic, enrichment reclassifying VUSs.The 1 689 845 ranging age 0 89 years at time (median age, 50 years), with 203 210 (71.2%) female individuals. There 39 150 Ashkenazi Jewish (2.3%), 64 730 Asian (3.8%), 126 739 Black (7.5%), 5539 French Canadian (0.3%), 169 714 Hispanic (10.0%), 5058 Native American 2696 Pacific Islander (0.2%), 4842 Sephardic 974 383 White (57.7%). Among all tested, 692 227 (41.0%) had least 535 385 (31.7%) only results. The number per individual increased more most missense changes (86.6%). More observed sequenced who not a European population, middle-aged older adults, underwent disorders incomplete penetrance. Of 37 699 unique that reclassified, 30 239 (80.2%) ultimately categorized benign. mean (SD) 30.7 (20.0) months elapsed be benign, 22.4 (18.9) pathogenic. Clinical contributed reclassification.This approximately 1.6 million highlighted need better methods interpreting variants, availability experimental classification, diverse representation groups genomic databases. this could provide sound basis understanding sources resolution navigating appropriate next steps patient care.

Язык: Английский

Процитировано

87
CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods DOI Creative Commons
Shantanu Jain, Constantina Bakolitsa, Steven E. Brenner

и другие.

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Фев. 22, 2024

Abstract Background The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction genetic variant impact, particularly where relevant disease. five complete editions CAGI community experiment comprised 50 challenges, in which participants made blind predictions phenotypes from data, and these were evaluated by independent assessors. Results Performance was strong clinical pathogenic variants, including some difficult-to-diagnose cases, extends interpretation cancer-related variants. Missense methods able estimate biochemical effects with increasing accuracy. regulatory variants complex trait disease risk less definitive indicates performance potentially suitable auxiliary use clinic. Conclusions show that while current are imperfect, they have major utility research applications. Emerging increasingly large, robust datasets training assessment promise further progress ahead.

Язык: Английский

Процитировано

37
Deciphering the impact of genomic variation on function DOI
J Engreitz, Heather A. Lawson, Harinder Singh

и другие.

Nature, Год журнала: 2024, Номер 633(8028), С. 47 - 57

Опубликована: Сен. 4, 2024

Язык: Английский

Процитировано

20
Saturation genome editing-based clinical classification of BRCA2 variants DOI
Sounak Sahu, Mélissa Galloux,

Eileen Southon

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Язык: Английский

Процитировано

2
Functional evaluation and clinical classification of BRCA2 variants DOI Creative Commons
Huaizhi Huang, Chunling Hu, Jie Na

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers1–5. However, variants of uncertain significance limit the utility test results. Thus, there is a need for functional characterization and classification all facilitate management individuals with these variants. Here we analysed possible single-nucleotide from exons 15 26 that encode DNA-binding domain hotspot pathogenic missense To enable this, used saturation genome editing CRISPR–Cas9-based knock-in endogenous targeting human haploid HAP1 cells6. The assay was calibrated relative nonsense silent validated using benign standards ClinVar results homology-directed repair assay7. Variants (6,959 out 6,960 evaluated) were assigned seven categories pathogenicity based on VarCall Bayesian model8. Single-nucleotide loss-of-function associated increased risks breast cancer ovarian cancer. integrated into models ClinGen, American College Medical Genetics Genomics, Association Molecular Pathology9 Using this approach, 91% classified as or likely benign. These improve variant. Results comprehensive evaluation particularly significance, provide useful resource who carry such

Язык: Английский

Процитировано

2
Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation DOI Creative Commons
Elizabeth J. Radford,

Hong-Kee Tan,

Malin H. L. Andersson

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 6, 2023

Loss-of-function of DDX3X is a leading cause neurodevelopmental disorders (NDD) in females. also somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing DDX3X, testing vitro the functional impact 12,776 nucleotide variants. identify 3432 functionally abnormal variants, three distinct classes. train machine learning classifier variants NDD-relevance. This has at least 97% sensitivity 99% specificity detect pathogenic for NDD, substantially out-performing silico predictors, resolving up 93% uncertain significance. Moreover, functionally-abnormal can account almost all excess nonsynonymous somatic mutations seen DDX3X-driven cancers. Systematic maps variant effects generated experimentally tractable cell types potential transform clinical interpretation both germline disease-associated variation.

Язык: Английский

Процитировано

33
Will variants of uncertain significance still exist in 2030? DOI Creative Commons
Douglas M. Fowler, Heidi L. Rehm

The American Journal of Human Genetics, Год журнала: 2023, Номер 111(1), С. 5 - 10

Опубликована: Дек. 11, 2023

Язык: Английский

Процитировано

32
ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification DOI Creative Commons

Leslie G. Biesecker,

Alicia B. Byrne,

Steven M Harrison

и другие.

The American Journal of Human Genetics, Год журнала: 2023, Номер 111(1), С. 24 - 38

Опубликована: Дек. 15, 2023

Язык: Английский

Процитировано

28