Colorado Care Network

7. A VUS is not a diagnosis

Clinicians with complex patients Planned episode, genetics in practice. Handling VUS results in primary care.

Listener title: A VUS is not a diagnosis: uncertain results in primary care

Listener description: A genetic counselor explains how to talk about a variant of uncertain significance so the patient does not leave thinking they have a diagnosis. The episode covers who follows up when a variant is reclassified, and how to keep care tied to the patient's own history rather than the variant. For primary care and specialty clinicians who receive genetic test reports.

Run of show (about 40 minutes)

Time Segment What happens
0:00 to 2:00 Opening The host introduces the topic and the guest's role. The guest discloses any industry relationships. The host notes that no patient information is discussed and that the guest speaks for themselves, not for the network.
2:00 to 11:00 Explaining a VUS How does the guest explain a VUS so the patient does not hear "diagnosis"? The guest explains where "uncertain significance" sits among the five standard classification terms (Richards 2015) and what a nine-laboratory study of those criteria showed about classifying the same variant (Amendola 2016). Which words help in the first minute, and which does a patient tend to carry home?
11:00 to 19:00 Composite scenario, not a real patient The host states that this is a composite scenario, not a real patient. An adult in primary care brings a multigene panel report with no pathogenic findings and one VUS. The patient has read about the gene online, is worried, and asks what to do and whether relatives should be tested. The host and guest walk through the conversation: what the clinician says, what goes in the chart, and when to bring in a genetic counselor.
19:00 to 28:00 Who follows up on reclassification Who owns the follow-up when a VUS may be reclassified: the laboratory, the ordering clinician, the patient or a counselor? The guest explains what the ACMG points-to-consider statement on reevaluation (Deignan 2019) says about how updated reports are sent, including when the ordering clinician is no longer involved, and what Mersch 2018 reported about how often VUS results were reclassified at one large laboratory, and in which direction. What can a small practice set up so a reclassification is not missed?
28:00 to 36:00 Treating the patient, not the variant How does the guest keep management tied to the personal and family history rather than the variant? What happens when a specialist, or the patient, wants to act on a VUS? How does the guest respond when the family history is concerning on its own, whatever the result says?
36:00 to 40:00 Closing One practical takeaway: the guest names one documentation habit for a VUS, and the host connects it to the network's comprehensive genetic risk care map, which records an explicit decision not to act on a VUS and a date the result will be reviewed. To reach the network, email hello@coloradocarenetwork.com or visit coloradocarenetwork.com/join. To suggest an episode, send the question in two sentences to the same address; members can also post it in #podcast on Slack.

Guest prep questions (sent to the guest a week ahead)

  1. What words do you use to explain a VUS in the first minute, and which do you avoid?
  2. When a laboratory reclassifies a variant, how does the update reach you, the ordering clinician and the patient, and where does that chain tend to break?
  3. In a small primary care practice, who should own reclassification follow-up, and what should they write down?
  4. Speaking about process only, with no patient details, where have you seen a VUS lead to testing or treatment that the personal and family history did not support, and what would have prevented it?
  5. When should a primary care clinician refer a patient with a VUS to a genetic counselor, and what should the referral ask?

Show notes

This episode is about the variant of uncertain significance in primary care. A genetic counselor explains how to describe a VUS so it is not heard as a diagnosis, with reference to the ACMG-AMP classification terms and a study of how consistently nine laboratories applied them. The conversation covers who follows up on reclassification, drawing on the ACMG statement on reevaluation and a study of variant reclassification after hereditary cancer testing, and how to keep care tied to the patient's history rather than the variant. A composite scenario, not a real patient, frames the middle of the episode.

  • Sources:
  • Richards S, Aziz N, Bale S, 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(5):405-424. doi:10.1038/gim.2015.30
  • Amendola LM, Jarvik GP, Leo MC, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet. 2016;98(6):1067-1076. doi:10.1016/j.ajhg.2016.03.024
  • Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274. doi:10.1001/jama.2018.13152
  • Deignan JL, Chung WK, Kearney HM, et al. Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21(6):1267-1270. doi:10.1038/s41436-019-0478-1
  • No patient information is discussed on this episode.

All planned episodes. To be the guest for this episode, email hello@coloradocarenetwork.com with the episode number.

Colorado Care Network. 7. A VUS is not a diagnosis. Version 2026-10-30.