Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul;25(7):100837.
doi: 10.1016/j.gim.2023.100837. Epub 2023 Apr 11.

Clinical implications of conflicting variant interpretations in the cancer genetics clinic

Elyssa Zukin  1 , Julie O Culver  2 , Yuxi Liu  3 , Yunqi Yang  4 , Charité N Ricker  2 , Rachel Hodan  5 , Duveen Sturgeon  6 , Kerry Kingham  5 , Nicolette M Chun  5 , Courtney Rowe-Teeter  5 , Kathryn Singh  7 , Jason A Zell  7 , Uri Ladabaum  5 , Kevin J McDonnell  6 , James M Ford  5 , Giovanni Parmigiani  3 , Danielle Braun  3 , Allison W Kurian  5 , Stephen B Gruber  6 , Gregory E Idos  8
Affiliations

Clinical implications of conflicting variant interpretations in the cancer genetics clinic

Elyssa Zukin et al. Genet Med. 2023 Jul.

Abstract

Purpose: The aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants.

Methods: Results from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic 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: Fifty of 975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a pathogenic/likely pathogenic variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10 of 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 used 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: Cancer genetics; ClinVar; Conflicting variant interpretation; Genetic counseling; Variant interpretation discrepancy.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Gregory E. Idos reports research funding from Myriad Genetics (Inst). Jason A. Zell serves in a consulting role for Tempus. Charité N. Ricker reports research funding from Myriad Genetics (Inst). Kevin J. McDonnell has served in a consulting or advisory role for Brogent International and reports research funding from Myriad Genetics. Uri Ladabaum serves as an advisor for Universal Dx, Lean Medical, Kohler Ventures, Vivante, and a consultant for Freenome, Guardant, Medtronic, Neptune Medical, Medial EarlySign. Stephen B. Gruber reports that he is co-founder with equity with Brogent International. Giovanni Parimigiani reports that he holds equity as a co-founder in Phaeno Biotechnologies, is on the SAB of Realm Idx (which owns Ambry Genetics) and currently consults for Delphi Diagnostics and (pro bono) for Martingale Labs. He also co-leads the BayesMendel laboratory, which licenses the BayesMendel package which include several ML tools for the computation of carrier probability of cancer susceptibility genes and future cancer risk. He does not derive any personal income from these licenses. Danielle Braun co-leads the BayesMendel lab, which develops and maintains the BayesMendel software package. This includes a variety of risk assessment tools, including BRCAPRO, PancPRO, MelaPRO, MMRpro and is licensed for commercial use. All other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Variant evaluation flowchart.
The 1,326 variant calls were evaluated individually to determine whether there was a clinically significant conflict among major commercial laboratories at the time of the specific patient’s report. Final conflicts are shown in the red box and represent conflicts among major laboratories as outlined by criteria in the Methods. *ClinVar archive search required for the other 65 variants.
Figure 2.
Figure 2.. Distribution of variants with clinically significant conflicts.
The 50 patients with variants that had clinically significant discrepant classifications are distributed by unique variant and aggregated by gene. The order of variants in the key corresponds to the vertical order of variants in the graph.
Figure 3.
Figure 3.. Suspicion of pathogenicity in patients with variants classified as VUS.
N=28. The number of patients with each variant for which there was and was not evidence of provider suspicion of pathogenicity is shown.
See this image and copyright information in PMC

References

    1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine : official journal of the American College of Medical Genetics 2015;17(5):405–424. - PMC - PubMed
    1. NCCN. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2022) 2021. (August 11th, 2021). https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. - PubMed
    1. NCCN. NCCN Genetic/Familial High-Risk Assessment: Colorectal 2021.
    1. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA-J Am Med Assoc 2010;304(9):967–975. - PMC - PubMed
    1. Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA-J Am Med Assoc 2006;296(12):1507–1517. - PubMed

Publication types