Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Challenges in genetic testing: clinician variant interpretation processes and the impact on clinical care



Efforts have been made to standardize laboratory variant interpretation, but clinicians are ultimately tasked with clinical correlation and application of genetic test results in patient care. This study aimed to explore processes clinicians utilize when reviewing and returning genetic test results, and how they impact patient care.


Medical geneticists, genetic counselors, and nongenetics clinicians from two Midwestern states completed surveys (n = 98) and in-depth interviews (n = 29) on practices of reviewing and returning genetic test results. Retrospective chart review (n = 130) examined discordant interpretations and the impact on care.


Participants reported variable behaviors in both reviewing and returning results based on factors such as confidence, view of role, practice setting, and relationship with the lab. Providers did not report requesting changes to variant classifications from laboratories, but indicated relaying conflicting classifications to patients in some cases. Chart reviews revealed medically impactful differences in interpretation between laboratories and clinicians in 18 (13.8%) records.


Clinician practices for reviewing and integrating genetic test results into patient care vary within and between specialties and impact patient care. Strategies to better incorporate both laboratory and clinician expertise into interpretation of genetic results could result in improved care across providers and settings.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Participant survey responses on frequency of returning genetic testing results and resources used in revewing genetic testing results.

Data availability

De-identified data are available by individual request.


  1. 1.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  2. 2.

    Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet. 2016;99:247.

    CAS  Article  Google Scholar 

  3. 3.

    Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat. 2018;39:1517–24.

    Article  Google Scholar 

  4. 4.

    ClinGen. Variant pathogenicity curation documents. Accessed 1 February 2021.

  5. 5.

    Bland A, Harrington EA, Dunn K, Pariani M, Platt J, Grove ME, et al. Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience. Genet Med. 2018;20:369–73.

    Article  Google Scholar 

  6. 6.

    Furqan A, Arscott P, Girolami F, Cirino AL, Michels M, Day SM, et al. Care in specialized centers and data sharing increase agreement in hypertrophic cardiomyopathy genetic test interpretation. Circ Cardiovasc Genet. 2017;10:e001700.

  7. 7.

    Zirkelbach E, Hashmi S, Ramdaney A, Dunnington L, Ashfaq M, Nugent EK, et al. Managing variant interpretation discrepancies in hereditary cancer: clinical practice, concerns, and desired resources. J Genet Couns. 2018;27:761–9.

    Article  Google Scholar 

  8. 8.

    Ackerman JP, Bartos DC, Kapplinger JD, Tester DJ, Delisle BP, Ackerman MJ. The promise and peril of precision medicine: phenotyping still matters most. Mayo Clin Proc. 2016;S0025-6196:30463.

    Google Scholar 

  9. 9.

    Baldridge D, Heeley J, Vineyard M, Manwaring L, Toler TL, Fassi E, et al. The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. Genet Med. 2017;19:1040–8.

    CAS  Article  Google Scholar 

  10. 10.

    Reuter C, Grove ME, Orland K, Spoonamore K, Caleshu C. Clinical cardiovascular genetic counselors take a leading role in team-based variant classification. J Genet Couns. 2018;27:751–60.

    Article  Google Scholar 

  11. 11.

    Wain KE, Azzariti DR, Goldstein JL, Johnson AK, Krautscheid P, Lepore B, et al. Variant interpretation is a component of clinical practice among genetic counselors in multiple specialties. Genet Med. 2020;22:785–92.

    CAS  Article  Google Scholar 

  12. 12.

    Biesecker LG, Biesecker BB. An approach to pediatric exome and genome sequencing. Curr Opin Pediatr. 2014;26:639–45.

    CAS  Article  Google Scholar 

  13. 13.

    Mazzola SE, O’Connor B, Yashar BM. Primary care physicians’ understanding and utilization of pediatric exome sequencing results. J Genet Couns. 2019;28:1130–8.

    Article  Google Scholar 

  14. 14.

    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81.

    Article  Google Scholar 

  15. 15.

    Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208.

    Article  Google Scholar 

  16. 16.

    IBM Corp. SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp. 2016.

  17. 17.

    Saldana J. The coding manual for qualitative researchers. 3rd edition. Thousand Oaks, CA: SAGE Publications; 2015.

  18. 18.

    Biesecker LG, Nussbaum RL, Rehm HL. Distinguishing variant pathogenicity from genetic diagnosis: how to know whether a variant causes a condition. JAMA. 2018;320:1929–30.

    Article  Google Scholar 

  19. 19.

    Helm BM, Ayers MD, Kean AC. All along the watchtower: a case of long QT syndrome misdiagnosis secondary to genetic testing misinterpretation. J Genet Couns. 2018;27:1515–22.

    Article  Google Scholar 

  20. 20.

    Macklin SK, Jackson JL, Atwal PS, Hines SL. Physician interpretation of variants of uncertain significance. Fam Cancer. 2018;18:121–6.

    Article  Google Scholar 

  21. 21.

    Donohue KE, Gooch C, Katz A, Wakelee J, Slavotinek A, Korf BR. Pitfalls and challenges in genetic test interpretation: an exploration of genetic professionals experience with interpretation of results. Clin Genet. 2021;99:638–49.

    CAS  Article  Google Scholar 

  22. 22.

    Marchant G, Barnes M, Evans JP, LeRoy B, Wolf SM. LawSeq Liability Task Force. From genetics to genomics: facing the liability implications in clinical care. J Law Med Ethics. 2020;48:11–43.

    Article  Google Scholar 

  23. 23.

    Wain KE, Palen E, Savatt JM, Shuman D, Finucane B, Seeley A, et al. The value of genomic variant ClinVar submissions from clinical providers: beyond the addition of novel variants. Hum Mutat. 2018;39:1660–67.

    Article  Google Scholar 

  24. 24.

    Segal MM. Genome interpretation: clinical correlation is recommended. Appl Transl Genom. 2015;6:26–27.

    Article  Google Scholar 

Download references


We thank the participants in the survey and interviews for sharing their behaviors and experiences. This work was funded by a Chairman’s Award from Children’s Mercy Hospital and by Genomic Answers for Kids.

Author information




Conceptualization: C.B., E.A.H., L.W., K.G., E.F. Data curation: C.B., E.A.H., E.F. Formal analysis: C.B., E.A.H., E.F. Funding acquisition: T.P., E.F. Investigation: C.B., E.A.H., E.F. Methodology: C.B., E.A.H., L.W., I.T., C.S., K.G., E.F. Project administration: C.B., E.A.H., E.F. Supervision: T.P., K.G., E.F. Visualization: C.B., E.F. Writing—original draft: C.B., E.F. Writing—review and editing: C.B., E.A.H., I.T., C.S., K.G., E.F.

Corresponding author

Correspondence to Courtney Berrios.

Ethics declarations


All studies were approved by the Children’s Mercy Institutional Review Board (IRB) (#17080496 and #1701332). Informed consent was obtained from all survey and interview participants as required by the IRB, with a waiver of documentation of informed consent. Data for the chart review were collected with a waiver of consent and HIPAA authorization granted by the IRB. Data collected in the survey were de-identified. Data collected in the interviews and chart review were de-identified for analysis, but links to identifiers were maintained.

Competing interests

E.F. is on a Clinical Expert Panel for Whole Genome Sequencing for Illumina, Inc., etc. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Berrios, C., Hurley, E.A., Willig, L. et al. Challenges in genetic testing: clinician variant interpretation processes and the impact on clinical care. Genet Med (2021).

Download citation


Quick links