Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing
Balmaña Gelpí, Judith (Hospital Universitari Vall d'Hebron)
Digiovanni, Laura (University of Pennsylvania, Philadelphia, PA)
Gaddam, Pragna (Memorial Sloan Kettering Cancer Center)
Walsh, Michael F. (Memorial Sloan Kettering Cancer Center)
Joseph, Vijai (Memorial Sloan Kettering Cancer Center)
Stadler, Zsofia K. (Memorial Sloan Kettering Cancer Center)
Nathanson, Katherine L. (University of Pennsylvania, Philadelphia, PA)
Garber, Judy (Dana-Farber Cancer Institute (Boston, Estats Units d'Amèrica))
Couch, Fergus J. (Mayo Clinic, Rochester, MN)
Offit, Kenneth (Memorial Sloan Kettering Cancer Center)
Robson, Mark E. (Memorial Sloan Kettering Cancer Center)
Domchek, Susan M. (University of Pennsylvania, Philadelphia, PA)
Universitat Autònoma de Barcelona

Data:	2016
Resum:	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. 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. 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. Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.
Nota:	Altres ajuts: Ambry Genetics, Myriad Genetics, Novartis (I), Pfizer (I)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of clinical oncology, Vol. 34 (september 2016) , p. 4071-4078, ISSN 1527-7755

DOI: 10.1200/JCO.2016.68.4316
PMID: 27621404

10 p, 806.8 KB

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