Toward automation of germline variant curation in clinical cancer genetics Journal Article


Authors: Ravichandran, V.; Shameer, Z.; Kemel, Y.; Walsh, M.; Cadoo, K.; Lipkin, S.; Mandelker, D.; Zhang, L.; Stadler, Z.; Robson, M.; Offit, K.; Vijai, J.
Article Title: Toward automation of germline variant curation in clinical cancer genetics
Abstract: Purpose: Cancer care professionals are confronted with interpreting results from multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches and aggregation of multiple lines of evidence from diverse resources. The clinical genetics community needs a fast algorithm that automates American College of Medical Genetics and Genomics (ACMG) based variant classification and provides uniform results. Methods: Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein, and disease specific information from public sources. We compared expertly curated variant data from clinical laboratories to assess performance. Results: PathoMAN achieved a high overall concordance of 94.4% for pathogenic and 81.1% for benign variants. We observed negligible discordance (0.3% pathogenic, 0% benign) when contrasted against expert curated variants. Some loss of resolution (5.3% pathogenic, 18.9% benign) and gain of resolution (1.6% pathogenic, 3.8% benign) were also observed. Conclusion: Automation of variant curation enables unbiased, fast, efficient delivery of results in both clinical and laboratory research. We highlight the advantages and weaknesses related to the programmable automation of variant classification. PathoMAN will aid in rapid variant classification by generating robust models using a knowledgebase of diverse genetic data (https://pathoman.mskcc.org). © 2019, American College of Medical Genetics and Genomics.
Keywords: germline; pathogenicity; cancer; acmg; curation
Journal Title: Genetics in Medicine
Volume: 21
Issue: 9
ISSN: 1098-3600
Publisher: Nature Publishing Group  
Date Published: 2019-09-01
Start Page: 2116
End Page: 2125
Language: English
DOI: 10.1038/s41436-019-0463-8
PUBMED: 30787465
PROVIDER: scopus
PMCID: PMC6703969
DOI/URL:
Notes: Article -- Correction issued, see DOI 10.1038/s41436-019-0490-5 -- Export Date: 2 December 2019 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    791 Offit
  2. Mark E Robson
    682 Robson
  3. Liying Zhang
    129 Zhang
  4. Zsofia Kinga Stadler
    395 Stadler
  5. Vijai Joseph
    213 Joseph
  6. Yelena Kemel
    106 Kemel
  7. Karen Anne Cadoo
    113 Cadoo
  8. Michael Francis Walsh
    156 Walsh
  9. Diana Lauren Mandelker
    183 Mandelker
  10. Zarina Shameer
    5 Zarina