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, 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.
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Judith
J
Balmaña
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Laura
L
Digiovanni
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Pragna
P
Gaddam
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Michael F
MF
Walsh
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Vijai
V
Joseph
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Zsofia K
ZK
Stadler
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Katherine L
KL
Nathanson
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Judy E
JE
Garber
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Fergus J
FJ
Couch
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Kenneth
K
Offit
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Mark E
ME
Robson
Judith Balmaña, Hospital Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Laura Digiovanni, Susan M. Domchek, and Katherine L. Nathanson, University of Pennsylvania, Philadelphia, PA; Pragna Gaddam, Michael F. Walsh, Vijai Joseph, Zsofia K. Stadler, Kenneth Offit, and Mark E. Robson, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA; and Fergus J. Couch, Mayo Clinic, Rochester, MN.
Susan M
SM
Domchek
D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000592:standards*; D014644:Genetic Variation; D005826:Genetics, Medical / Q000592:standards*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007753:Laboratories / Q000592:standards*; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D011446:Prospective Studies; D012042:Registries