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Clinician Survey on VUS Reporting in Panel Genetic Testing 

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
The field of genetic testing has evolved in the past decade, with broader clinical indications and more genes assessed in panels. The reporting practices have not evolved similarly, leading to high rates of variants of uncertain significance (VUS), many with low likelihood to be disease-causing. For exome sequencing analysis, reporting is focused on the clinical presentation and generally results in a limited number of variants. While few laboratories follow the same practice for panels, many laboratories still report all VUS, irrespective of inheritance or clinical phenotype, creating unnecessary burden on clinicians and patients. 

 

Methods:
We surveyed clinicians at Vanderbilt University Medical Center (VUMC) to determine their preferences for panel reporting of single VUS in genes associated with autosomal recessive (AR) disorders, autosomal dominant (AD) disorders, and in genes with limited disease association.  The survey was distributed through REDCAP, a secure web-based software platform to support data capture for research studies, and it was sent to 105 clinicians that had previously ordered genetic testing through the VUMC Clinical Genomics Laboratory.  

 

Results:
We received responses from 18 participants (17%), including 8 clinical geneticists and genetic counselors, as well as 10 clinical providers, primarily specialized in Cardiology and Neurology (non-geneticists). The clinicians’ answers were as follow: 

  1. One (5.5%) of the clinicians preferred not reporting single VUS in AR genes, 9 (50%) selected including these variants in an additional variants table without a detailed interpretation, 6 (33%) preferred having these variants fully reported, and 2 (11%) provided additional comments. Of note, 4 (66.6%) of the 6 participants who preferred having these variants reported were non-geneticists.  

  2. When asked about VUS in AR genes with weak evidence of pathogenicity and/or no phenotypic overlap, 9 (50%) of participants chose not reporting these variants, 5 (27.7%) selected including these variants in an additional variants table, while 3 (16.6%) preferred having these variants fully reported.  

  3. When asked about their preference on single VUS in an AR gene with strong evidence of pathogenicity and significant phenotypic overlap, 16 (88.9%) of the clinicians preferred reporting them, while 1 (5.5%) selected the additional variants table option, and 1 participant provided additional comments.  

  4. For VUS with weak evidence of pathogenicity in an AD gene, 9 (50%) chose to report these variants, and 9 (50%) preferred including these variants in an additional variants table, without a detailed interpretation.  

  5. For VUS in an AD gene with no or minimal phenotypic overlap, 11 (61%) preferred reporting these variants, 6 (33%) selected including these in an additional variants table, while 1 (5.5%) included additional comments.  

  6. For VUS in a gene with limited disease association and weak evidence of pathogenicity, 8 (44.4%) chose not reporting these variants, 6 (33%) selected included them in the additional variants table, while 3 (16.6%) clinicians preferred reporting these variants. 




Conclusion:
This survey provides insights into clinicians’ preferences on panel reporting for certain VUS and can help laboratories revisit their current panel reporting practices to reduce the number of reported VUS. A high percentage of providers opted towards not reporting single VUS in AR genes, and the percentage further increased for variants of low likelihood to be disease causing. A relatively high fraction of clinicians (61%) preferred reporting VUS in AD genes with no or minimal phenotypic overlap, suggesting that they prefer to perform the clinical correlation. Even though only 18 providers responded, their feedback represents a wide array of perspectives from both geneticists and non-geneticists. A large fraction of the clinicians surveyed were non-geneticists (80%), and it’s possible that less in-depth experience with genetic testing contributed to the lower response rate. 

 

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