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Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing
PURPOSE: Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and,...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Clinical Oncology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562435/ https://www.ncbi.nlm.nih.gov/pubmed/27621404 http://dx.doi.org/10.1200/JCO.2016.68.4316 |
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author | Balmaña, Judith Digiovanni, Laura Gaddam, Pragna Walsh, Michael F. Joseph, Vijai Stadler, Zsofia K. Nathanson, Katherine L. Garber, Judy E. Couch, Fergus J. Offit, Kenneth Robson, Mark E. Domchek, Susan M. |
author_facet | Balmaña, Judith Digiovanni, Laura Gaddam, Pragna Walsh, Michael F. Joseph, Vijai Stadler, Zsofia K. Nathanson, Katherine L. Garber, Judy E. Couch, Fergus J. Offit, Kenneth Robson, Mark E. Domchek, Susan M. |
author_sort | Balmaña, Judith |
collection | PubMed |
description | PURPOSE: Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. METHODS: Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. RESULTS: Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. CONCLUSIONS: Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions. |
format | Online Article Text |
id | pubmed-5562435 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society of Clinical Oncology |
record_format | MEDLINE/PubMed |
spelling | pubmed-55624352017-09-07 Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing Balmaña, Judith Digiovanni, Laura Gaddam, Pragna Walsh, Michael F. Joseph, Vijai Stadler, Zsofia K. Nathanson, Katherine L. Garber, Judy E. Couch, Fergus J. Offit, Kenneth Robson, Mark E. Domchek, Susan M. J Clin Oncol ORIGINAL REPORTS PURPOSE: Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. METHODS: Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. RESULTS: Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. CONCLUSIONS: Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions. American Society of Clinical Oncology 2016-12-01 2016-09-12 /pmc/articles/PMC5562435/ /pubmed/27621404 http://dx.doi.org/10.1200/JCO.2016.68.4316 Text en © 2016 by American Society of Clinical Oncology Licensed under the Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | ORIGINAL REPORTS Balmaña, Judith Digiovanni, Laura Gaddam, Pragna Walsh, Michael F. Joseph, Vijai Stadler, Zsofia K. Nathanson, Katherine L. Garber, Judy E. Couch, Fergus J. Offit, Kenneth Robson, Mark E. Domchek, Susan M. Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing |
title | Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing |
title_full | Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing |
title_fullStr | Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing |
title_full_unstemmed | Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing |
title_short | Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing |
title_sort | conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing |
topic | ORIGINAL REPORTS |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562435/ https://www.ncbi.nlm.nih.gov/pubmed/27621404 http://dx.doi.org/10.1200/JCO.2016.68.4316 |
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