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

Judith Balmaña, Laura Digiovanni, Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Katherine L. Nathanson, Judy E. Garber, Fergus J Couch, Kenneth Offit, Mark E. Robson, Susan M. Domchek

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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.

Original languageEnglish (US)
Pages (from-to)4071-4078
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number34
DOIs
StatePublished - Dec 1 2016

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Registries
Genetic Testing
Neoplasms
Guidelines
High-Throughput Nucleotide Sequencing
Cohort Studies
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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.

In: Journal of Clinical Oncology, Vol. 34, No. 34, 01.12.2016, p. 4071-4078.

Research output: Contribution to journalArticle

Balmaña, J, Digiovanni, L, Gaddam, P, Walsh, MF, Joseph, V, Stadler, ZK, Nathanson, KL, Garber, JE, Couch, FJ, Offit, K, Robson, ME & Domchek, SM 2016, 'Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing', Journal of Clinical Oncology, vol. 34, no. 34, pp. 4071-4078. https://doi.org/10.1200/JCO.2016.68.4316
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. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 34. pp. 4071-4078.
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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.",
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AU - Balmaña, Judith

AU - Digiovanni, Laura

AU - Gaddam, Pragna

AU - Walsh, Michael F.

AU - Joseph, Vijai

AU - Stadler, Zsofia K.

AU - Nathanson, Katherine L.

AU - Garber, Judy E.

AU - Couch, Fergus J

AU - Offit, Kenneth

AU - Robson, Mark E.

AU - Domchek, Susan M.

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N2 - 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.

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