Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar
Open accessAbstract
Purpose Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants. Methods ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations. Results At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines. Conclusion Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar-thereby allowing identification of differences and motivation to resolve those differences-is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Accepted standards for concordance do not exist, and variability among laboratories has been observed.
“Accepted standards for concordance do not exist, and variability among laboratories has been observed.7”
From Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria (2022) · cites this paper as [7]
The Results (Initial Concordance Data; page unavailable) report that 11.7% of shared variants had discordant interpretations, supporting observed variability among laboratories. The paper does not establish that accepted standards for concordance do not exist; it describes the criteria used for this project instead. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
Self-citationAnalysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
ClinVar: public archive of interpretations of clinically relevant variants
Landrum, M. J., Lee, J. M., Benson, M., Brown, G., Chao, C., Chitipiralla, S., Gu, B., Hart, J., Hoffman, D., Hoover, J., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1222 · Cited by 2,758 · see citing works
ClinGen — The Clinical Genome Resource
Rehm, H. L., Berg, J. S., Brooks, L. D., Bustamante, C. D., Evans, J. P., Landrum, M. J., Ledbetter, D. H., Maglott, D. R., Martin, C. L., Nussbaum, R. L., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmsr1406261 · Cited by 1,496 · see citing works
Self-citationDiagnostic Concordance Among Pathologists Interpreting Breast Biopsy Specimens
Elmore, J. G., Longton, G. M., Carney, P. A., Geller, B. M., Onega, T., Tosteson, A. N. A., Nelson, H. D., Pepe, M. S., Allison, K. H., Schnitt, S. J., et al. (2015) · JAMA · doi:10.1001/jama.2015.1405 · Cited by 751 · see citing works
Amendola, L. M., Jarvik, G. P., Leo, M. C., McLaughlin, H. M., Akkari, Y. M. N., Amaral, M. D., Berg, J. S., Biswas, S., Bowling, K. M., Conlin, L. K., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.03.024 · Cited by 556 · see citing works
Self-citationInSiGHT, O. B. O., Thompson, B. A., Spurdle, A. B., Plazzer, J., Greenblatt, M. S., Akagi, K., Al‐Mulla, F., Bapat, B. V., Bernstein, I., Capellá, G., et al. (2013) · Nature Genetics · doi:10.1038/ng.2854 · Cited by 468 · see citing works
Actionable exomic incidental findings in 6503 participants: challenges of variant classificationPreprint
Amendola, L. M., Dorschner, M. O., Robertson, P. D., Salama, J. S., Hart, R., Shirts, B. H., Murray, M. L., Tokita, M., Gallego, C. J., Kim, D. S., et al. (2015) · Genome Research · doi:10.1101/gr.183483.114 · Cited by 361 · see citing works
Self-citationSpurdle, A. B., Healey, S. C., Devereau, A. D., Hogervorst, F. B. L., Monteiro, Á. N. A., Nathanson, K. L., Radice, P., Stoppa‐Lyonnet, D., Tavtigian, S. V., Wappenschmidt, B., et al. (2011) · Human Mutation · doi:10.1002/humu.21628 · Cited by 308 · see citing works
Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants
Jarvik, G. P., & Browning, B. L. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.04.003 · Cited by 271 · see citing works
Variation in Mammographic Breast Density Assessments Among Radiologists in Clinical Practice
Sprague, B. L., Conant, E. F., Onega, T., Garcia, M. P., Beaber, E. F., Herschorn, S. D., Lehman, C. D., Tosteson, A. N. A., Lacson, R. C., Schnall, M. D., et al. (2016) · Annals of Internal Medicine · doi:10.7326/m15-2934 · Cited by 205 · see citing works
Balmañà, J., DiGiovanni, L., Gaddam, P., Walsh, M. F., Vijai, J., Stadler, Z. K., Nathanson, K. L., Garber, J. E., Couch, F. J., Offit, K., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.68.4316 · Cited by 171 · see citing works
Green, R. C., Goddard, K. A. B., Jarvik, G. P., Amendola, L. M., Appelbaum, P. S., Berg, J. S., Bernhardt, B. A., Biesecker, L. G., Biswas, S., Zawatsky, C. L. B., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.04.011 · Cited by 155 · see citing works
Self-citationAmendola, L. M., Jarvik, G. P., Leo, M. C., McLaughlin, H. M., Akkari, Y. M. N., Amaral, M. D., Berg, J. S., Biswas, S., Bowling, K. M., Conlin, L. K., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.06.001 · Cited by 142 · see citing works
Self-citationMaxwell, K. N., Hart, S. N., Vijai, J., Schrader, K. A., Slavin, T. P., Thomas, T., Wubbenhorst, B. S., Ravichandran, V., Moore, R. M., Hu, C., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.02.024 · Cited by 129 · see citing works
Pepin, M. G., Murray, M. L., Bailey, S. S., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.31 · Cited by 71 · see citing works
Use of panel tests in place of single gene tests in the cancer genetics clinic
Yorczyk, A., Robinson, L. S., & Ross, T. S. (2014) · Clinical Genetics · doi:10.1111/cge.12488 · Cited by 49 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Srivastava, S., Love-Nichols, J. A., Dies, K. A., Ledbetter, D. H., Martin, C. L., Chung, W. K., Firth, H. V., Frazier, T., Hansen, R. L., Prock, L., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0554-6 · Cited by 695 · see citing works
Pejaver, V., Byrne, A. B., Feng, B.-J., Pagel, K. A., Mooney, S. D., Karchin, R., O’Donnell-Luria, A., Harrison, S. M., Tavtigian, S. V., Greenblatt, M. S., et al. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.10.013 · Cited by 589 · see citing works
“7 Finally, the design of several tools was motivated mainly by the discovery of novel variants and hypothesis generation for experimental follow-up, rather than clinical pathogenicity clas-sification.”
MethodSelf-citationTandy-Connor, S., Guiltinan, J., Krempely, K., LaDuca, H., Reineke, P., Gutierrez, S., Gray, P., & Tippin Davis, B. (2018) · Genetics in Medicine · doi:10.1038/gim.2018.38 · Cited by 273 · see citing works
Volpi, S., Bult, C. J., Chisholm, R. L., Deverka, P. A., Ginsburg, G. S., Jacob, H. J., Kasapi, M., McLeod, H. L., Roden, D. M., Williams, M. S., et al. (2018) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1048 · Cited by 135 · see citing works
Self-citation
- Authors
- Harrison, S. M., Dolinsky, J. S., Knight Johnson, A. E., Pesaran, T., Azzariti, D. R., Bale, S., Chao, E. C., Das, S., Vincent, L., & Rehm, H. L.
- Affiliations
- Harvard University (US)
- Ambry Genetics (United States) (US)
- University of California, Irvine (US)
- University of Chicago (US)
- Broad Institute (US)
- Corresponding author
- Harrison, Steven M.
- ORCID
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 19
- Issue
- 10
- Pages
- 1096-1104
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC5600649
- OpenAlex
- W2595455619
- Cited by
- 234
- References
- 18
- Citations by year
- 2026: 17 · 2025: 14 · 2024: 19 · 2023: 16 · 2022: 22 · 2021: 29 · 2020: 21 · 2019: 33 · 2018: 44 · 2017: 18 · 2016: 1
- FWCI
- 20.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Human Genome Research Institute (U41HG006834)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Keywords
- ClinVar, variant interpretation, data sharing, ACMG/AMP guidelines, clinical laboratory, concordance, ClinGen
- MeSH terms
- Clinical Laboratory Information Systems, Genetic Testing, Humans, Laboratories, Software, Genetic Variation, Genome, Human, Clinical Laboratory Techniques, Genomics, Databases, Genetic, Information Dissemination, High-Throughput Nucleotide Sequencing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
