Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team-based Variant Classification
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We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2 years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p < 0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work.
KeywordsVariant classification Cardiovascular Genetic testing Genetic counselor Genetic counseling Interpretation
We are grateful to the cardiovascular genetic counselors who participated in this study. KS is partially supported by the Indiana University Health – Indiana University School of Medicine Strategic Research Initiative.
Compliance with Ethical Standards
Conflicts of Interest
CR, KO, and MG declare that they have no conflict of interest.
CC has received honoraria for work as an advisor and/or consultant for Phosphorus, Recombine, Invitae, GeneDx, Gilead, Myokardia. She has also received royalties for a patent on genome interpretation technology and holds stock in Personalis.
KS has received honoraria for work as an Advisory Board member for Invitae.
Human Studies and Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
No animal studies were carried out by the authors for this article
- Amendola, L. M., Jarvik, G. P., Leo, M. C., McLaughlin, H. M., Akkari, Y., Amaral, M. D., et al. (2016). Performance of ACMG-AMP variant-interpretation guidelines among nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. The American Journal of Human Genetics, 98(6), 1067–1076. https://doi.org/10.1016/j.ajhg.2016.03.024.CrossRefPubMedGoogle Scholar
- Andreasen, C., Nielsen, J. B., Refsgaard, L., Holst, A. G., Christensen, A. H., Andreasen, L., et al. (2013). New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. European Journal of Human Genetics : EJHG, 21(9), 918–928. https://doi.org/10.1038/ejhg.2012.283.CrossRefPubMedGoogle Scholar
- Balmana, J., Digiovanni, L., Gaddam, P., Walsh, M. F., Joseph, V., Stadler, Z. K., et al. (2016). Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. Journal of Clinical Oncology, 34(34), 4071–4078. https://doi.org/10.1200/JCO.2016.68.4316.CrossRefPubMedPubMedCentralGoogle Scholar
- Bland, A., Dunn, K. E., Pariani, M., Platt, J., Grove, M. E., & Caleshu, C. (2016). Abstract: A single-center experience with clinician interpretation of variants in cardiovascular genetics indicates clinically impactful disagreement with testing laboratories. Journal of Genetic Counseling, 25(6), 1347–1472.CrossRefGoogle Scholar
- Caleshu, C., & Ashley, E. A. (2016). Taming the genome : Towards better genetic test interpretation. Genome Medicine, 9–11. https://doi.org/10.1186/s13073-016-0325-9.
- Caleshu, C., Kasparian, N. A., Edwards, K. S., Yeates, L., Semsarian, C., Perez, M., et al. (2016a). Interdisciplinary psychosocial care for families with inherited cardiovascular diseases. Trends in Cardiovascular Medicine, 26(7), 647–653. https://doi.org/10.1016/j.tcm.2016.04.010.CrossRefPubMedGoogle Scholar
- Caleshu, C., Kelly, M., Morales, A., Ashley, E., Hershberger, R., & Funke, B. (2016b). Lack of specificity of ACMG classification rules decreases inter-curator concordance. ClinGen’s adaptation of ACMG’s framework to standardize interpretation of MYH7 related cardiomyopathy variants., (ASHG Annual Meeting). Retrieved from http://www.ashg.org/2015meeting/pdf/57715_Posters.pdf
- Erskine, K. E., Griffith, E., Degroat, N., Stolerman, M., Silverstein, L. B., Hidayatallah, N., et al. (2013). An interdisciplinary approach to personalized medicine : Case studies from a cardiogenetics clinic P erspective. Personalized Medicine, 10(1), 73–80.CrossRefPubMedPubMedCentralGoogle Scholar
- Furqan, A., Arscott, P., Girolami, F., Cirino, A. L., Michels, M., Day, S. M., et al. (2017). Care in Specialized Centers and Data Sharing Increase Agreement in hypertrophic cardiomyopathy genetic test interpretation. Circulation. Cardiovascular Genetics, 10(5), e001700. https://doi.org/10.1161/CIRCGENETICS.116.001700.CrossRefPubMedGoogle Scholar
- Garber, K. B., Vincent, L. M., Alexander, J. J., Bean, L. J. H., Bale, S., & Hegde, M. (2016). Reassessment of genomic sequence variation to harmonize interpretation for personalized medicine. American Journal of Human Genetics, 99(5), 1140–1149. https://doi.org/10.1016/j.ajhg.2016.09.015.CrossRefPubMedPubMedCentralGoogle Scholar
- Harrison, S. M., Dolinsky, J. S., Knight Johnson, A. E., Pesaran, T., Azzariti, D. R., Bale, S., et al. (2017). Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. American College of Medical Genetics and Genomics: Genet Med Retrieved from https://doi.org/10.1038/gim.2017.14.Google Scholar
- Ingles, J., Lind, J. M., Phongsavan, P., & Semsarian, C. (2008). Psychosocial impact of specialized cardiac genetic clinics for hypertrophic cardiomyopathy. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 10(2), 117–120. https://doi.org/10.1097/GIM.0b013e3181612cc7.CrossRefGoogle Scholar
- Kelly, M., Caleshu, C., Morales, A., Buchan, J., Wolf, Z., Cook, S., … Funke, B. (in press). Adaptation and Validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: Recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel. Genetics in Medicine.Google Scholar
- Kurian, A. W., Li, Y., Hamilton, A. S., Ward, K. C., Hawley, S. T., Morrow, M., et al. (2017). Gaps in incorporating Germline genetic testing into treatment decision-making for early-stage breast cancer. Journal of Clinical Oncology, 35(20), 2232–2239. https://doi.org/10.1200/JCO.2016.71.6480.CrossRefPubMedPubMedCentralGoogle Scholar
- Maron, B. J., Haas, T. S., Doerer, J. J., Thompson, P. D., & Hodges, J. S. (2009). Comparison of U.S. and Italian experiences with sudden cardiac deaths in young competitive athletes and implications for preparticipation screening strategies. The American Journal of Cardiology, 104(2), 276–280. https://doi.org/10.1016/j.amjcard.2009.03.037.CrossRefPubMedGoogle Scholar
- Rehm, H. L. (2017). A new era in the interpretation of human genomic variation. Genetics in Medicine, 1–4. https://doi.org/10.1038/gim.2017.90.
- Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., et al. (2015). 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, 17(5), 405–423. https://doi.org/10.1038/gim.2015.30.CrossRefPubMedPubMedCentralGoogle Scholar
- Shah, N., Hou, Y.-C. C., Yu, H.-C., Sainger, R., Dec, E., Perkins, B., … Telenti, A. (2016). Identification of misclassified ClinVar variants using disease population prevalence. bioRxiv. Retrieved from http://biorxiv.org/content/early/2016/09/15/075416.abstract
- Thompson, B. A., Spurdle, A. B., Plazzer, J.-P., Greenblatt, M. S., Akagi, K., Al-Mulla, F., et al. (2014). Application of a five-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants lodged on the InSiGHT locus-specific database. Nature Genetics, 46(2), 107–115. https://doi.org/10.1038/ng.2854.CrossRefPubMedGoogle Scholar
- Walsh, R., Thomson, K. L., Ware, J. S., Funke, B. H., Woodley, J., Mcguire, K. J., et al. (2016). Reassessment of Mendelian gene pathogenicity using 7, 855 cardiomyopathy cases and 60, 706 reference samples. Genetics in Medicine, 1–12. https://doi.org/10.1038/gim.2016.90.
- Yang, S., Lincoln, S. E., Kobayashi, Y., Nykamp, K., Nussbaum, R. L., & Topper, S. (2017). Sources of discordance among germ-line variant classifications in ClinVar, 1–9. https://doi.org/10.1038/gim.2017.60.