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Screening
Original research
Variant classification changes over time in the clinical molecular diagnostic laboratory setting
  1. Elan Hahn1,2,
  2. Chloe Mighton1,3,4,
  3. Yael Fisher1,
  4. Andrew Wong1,
  5. Vanessa Di Gioacchino1,5,
  6. Nicholas Watkins1,5,
  7. Justin Mayers1,
  8. Yvonne Bombard3,4,
  9. George S Charames1,2,6,
  10. Jordan Lerner-Ellis1,2,6
  1. 1 Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
  2. 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  3. 3 Genomics Health Services Research Program, St Michael's Hospital Li Ka Shing Knowledge Institute, Unity Health Toronto, Toronto, Ontario, Canada
  4. 4 Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
  5. 5 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  6. 6 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  1. Correspondence to Dr Jordan Lerner-Ellis, Mount Sinai Hospital Pathology and Laboratory Medicine, Toronto, Canada; jordan.lerner-ellis{at}sinaihealth.ca

Abstract

Background Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario.

Methods DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category).

Results Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%).

Conclusions The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.

  • Genetic Variation
  • Germ-Line Mutation
  • Clinical Decision-Making
  • Genetic Counselling
  • Genetic Predisposition to Disease

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2023-109772

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • EH and CM contributed equally.

    • Presented at This work was previously presented as an abstract at the Association for Molecular Pathology Annual Meeting, November 2023 (Hahn E, Mighton C, Fisher Y, et al. Variant classification changes over time at a clinical molecular diagnostic laboratory. J Mol Diagn 2023;25:S7. doi: 10.1016/S1525-1578(23)00249-0).

    • Correction notice This article has been corrected since it was published online first. An ORCID identifier has been added.

    • Contributors EH, CM and JL-E performed study concept and design; EH, CM, JL-E, YF, NW, JM and YB performed development of methodology and writing, review and revision of the paper; EH, CM, JL-E, YF, NW, JM, YB, GSC, VDG and AW provided acquisition, analysis and interpretation of data. All authors read and approved the final paper. JL-E is the guarantor of the publication.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.