By Eleanor Griffith

Once Burned, Twice Shy: Cardiovascular Genetics Clinicians Exercise Caution in Relying on Received Variant Classifications

At the recent 2017 Heart Rhythm Society conference, the clinical and counseling challenges posed by Variants of Uncertain Significance (VUS) was, not unexpectedly, a recurring theme, as were discordant classifications between laboratories and ordering clinicians.

  • Genetic Counselor Kyla Dunn, M.S., CGC said that reading a genetic test report was not a passive process, and that at her institution, genetic counselors often disagree with the reporting lab and need to seek out additional information. She shared an older case example of a variant that had been assigned classifications ranging from likely benign to pathogenic, saying that the updated 2015 ACMG guidelines have helped.
  • Dr. Heidi Rehm spoke to a study that compared different labs’ interpretations of certain variants and found only 34% concordance, even when using the same 2015 ACMG Guidelines.
  • Dr. Dominic Abrams pointed out that some variants that had been characterized as pathogenic in the past would signify a 1/30 disease prevalence, based on ExAC data available now. He cautioned that it’s important to be conservative in diagnosis, to require strong evidence for pathogenicity, and not implement cascade screening in its absence. He also called attention to the economic and societal costs if this more conservative approach is not taken.
  • Genetic Counselor Rebecca McClellan, M.G.C., CGC shared that Johns Hopkins takes a different approach and may still offer cascade testing even with a VUS, although uptake is low.
  • Genetic Counselor Brittney Murray, M.S., CGC gave examples of missense variants that were classified as pathogenic in 2006 and 2007 and were subsequently found in controls. She cautioned that interpretation of genetic test results received from a laboratory should be done with care by someone with a lot of background and expertise.
  • Alex Christensen, M.D., Ph.D. said that data from the Copenhagen City Heart Study suggests that 5-16% of the general population carries at least one variant in the desmosomal genes and recommended that phenotype should always guide gene selection instead of opting for a larger panel just because it’s an available option.
  • Peter van Tintelen, M.D., Ph.D. shared that, in his cardiogenetics program in Amsterdam, cascade screening is done for VUSs in affected persons only, as part of segregation studies.
  • Genetic Counselor Cynthia James, ScM., CGC, Ph.D. countered that Johns Hopkins does larger panels because they worry about missing mutations and want to rule out as many potentially pathogenic variants in a family as possible.
  • Genetic Counselor Chloe Reuter, M.S., CGC presented a poster on the results of a survey indicating that >95% of cardiovascular genetic counselors gather additional information on variants identified through clinical testing and that >81% of those who do so also perform their own variant classification assessment, most often in collaboration with a physician.

By ACMG Guidelines, 90% certainty is sufficient to warrant a classification of “likely pathogenic.” The same guidelines acknowledge that “at present, most variants do not have data to support a quantitative assignment of variant certainty” and point to the need for “statistical approaches to objectively assign pathogenicity confidence to variants.”

The ACMG guidelines also stress that the clinical application of genetic testing evidence is also dependent on the clinical context and indication for testing: “It is therefore critical for referring healthcare providers to communicate with the clinical laboratory to gain an understanding of how variants are classified to assist in patient counseling and management.”

At Phosphorus, we take a conservative and transparent approach to variant classification, making an effort to provide the data and the rationale behind the classification on the issued report and by strictly following ACMG guidelines. We would always prefer to receive as much information as possible about the individual or family you have identified as appropriate for testing–even if it doesn’t fit on a test requisition form. We welcome discussion with ordering providers at all points in the testing process.

We are looking for ways to facilitate better and easier communication: between ordering clinicians and the lab regarding phenotypic and family history information; between GCs and referring physicians; between clinicians working in multidisciplinary teams; between clinicians and their patients. Let us know how we can best partner with you to help you optimally manage your patients!

Eleanor is the Clinical Science Liaison at Phosphorus. You can reach her at eleanor@phosphorus.com to share ideas for improved partnership.


1.Genet Med. 2015 May; 17(5): 405–424. Published online 2015 Mar 5. doi: 10.1038/gim.2015.30

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