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Abstract
Purpose
To describe the clinical impact of commercial laboratories issuing conflicting classifications
of genetic variants.
Methods
Results from 2,000 patients undergoing a multi-gene hereditary cancer panel by a single
laboratory were analyzed. Clinically significant discrepancies between the lab provided
test reports and other major commercial laboratories were identified, including differences
between pathogenic/likely pathogenic (P/LP) and variant of uncertain significance
(VUS) classifications, via review of ClinVar archives. For patients carrying a VUS,
clinical documentation was assessed for evidence of provider awareness of the conflict.
Results
50/975 (5.1%) patients with non-negative results carried a variant with a clinically
significant conflict, 19 with a P/LP variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10/28 (36%) patients with a VUS with a clinically significant conflict had
a documented discussion by a provider about the conflict. Discrepant counseling strategies
were utilized for different patients with the same variant. Among patients with a
CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on
the laboratory-reported classification.
Conclusion
Our findings highlight the frequency of variant interpretation discrepancies and importance
of clinician awareness. Guidance is needed on managing patients with discrepant variants
to support accurate risk assessment.
Keywords
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Article info
Publication history
Accepted:
April 5,
2023
Received in revised form:
April 3,
2023
Received:
October 18,
2022
Publication stage
In Press Accepted ManuscriptIdentification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
