Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing Journal Article


Authors: Balmaña, J.; Digiovanni, L.; Gaddam, P.; Walsh, M. F.; Joseph, V.; Stadler, Z. K.; Nathanson, K. L.; Garber, J. E.; Couch, F. J.; Offit, K.; Robson, M. E.; Domchek, S. M.
Article Title: Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing
Abstract: 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 byRAD51C, 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. © 2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 34
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-12-01
Start Page: 4071
End Page: 4078
Language: English
DOI: 10.1200/jco.2016.68.4316
PROVIDER: scopus
PUBMED: 27621404
PMCID: PMC5562435
DOI/URL:
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Kenneth Offit
    497 Offit
  2. Mark E Robson
    360 Robson
  3. Zsofia Kinga Stadler
    140 Stadler
  4. Vijai Joseph
    114 Joseph
  5. Pragna   Gaddam
    9 Gaddam
  6. Michael Francis Walsh
    43 Walsh