A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients
| Autor: | Ana Vega, Orland Diez, Alejandro Moles-Fernández, Xavier de la Cruz, Gabriel Capellá, Luz-Marina Porras, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Daniel Rueda, Conxi Lázaro, Anael López-Novo, Clara Ruiz-Ponte, Marta Pineda, Ana Blanco, Ignacio J. Molina, Lídia Feliubadaló, Ana Osorio, Marta Santamariña-Pena, Alysson T Sánchez |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Computer science Clinical Biochemistry Genomics Computational biology Disease Ataxia Telangiectasia Mutated Proteins Spanish database 03 medical and health sciences 0302 clinical medicine Breast cancer Neoplasms medicine Malalties hereditàries Humans Genetic Predisposition to Disease ACMG/AMP guidelines Espanya Curació de dades Massive parallel sequencing Data curation Molecular pathology Biochemistry (medical) Genetic Variation High-Throughput Nucleotide Sequencing Cancer patients medicine.disease Hereditary cancer Data sharing Malalts de càncer 030104 developmental biology Spain 030220 oncology & carcinogenesis Variant classification Medical genetics Female Genetic diseases |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Digibug. Repositorio Institucional de la Universidad de Granada instname Digibug: Repositorio Institucional de la Universidad de Granada Universidad de Granada (UGR) |
| ISSN: | 1530-8561 |
| Popis: | Background Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene. Methods Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants. Results Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%. Conclusions Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management. FEDER funds-a way to build Europe PI19/00553 PI16/00563 PI16/01898 SAF2015-68016-R Generalitat de Catalunya 2017SGR1282 2017SGR496 CERCA Program: Government of Catalonia Xunta de Galicia Instituto de Salud Carlos III. AES PI19/00340 Spanish Government SAF2016-80255-R European Commission EFA086/15 Instituto de Salud Carlos III European Commission |
| Databáze: | OpenAIRE |
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