NGS-based Clinical Testing (Part VI)

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With a properly defined wet-lab and bioinformatics process, we are able to zero in on clinically relevant variants. How does a lab report on the outcome of their analysis? We find that most laboratories conduct their variant classification based on the guidelines formulated by the American College of Medical Genetics (ACMG) for inherited diseases. The ACMG guidelines for variant classification are regularly revised, so it’s important to stay abreast of new developments.

From our perspective, there is quite a variety of different reporting standards that we observe in practice for tumor and infectious pathogen diagnosis. The reporting on inherited diseases seems to be more consistent across the board. Typically variants are classified in the following way:

  • Pathogenic
  • Likely pathogenic
  • Uncertain clinical significance
  • Likely benign
  • Benign

In a recent meeting in Washington DC among leading clinicians in this field, it was mentioned many times that certain findings can be deceptive. For example, a novel loss-of-function variant, which is obviously a very damaging mutation in a gene, with no known connection to the observed phenotype needs to be handled very carefully. Chances are that the severe mutation has in fact nothing to do with the disease. Typically, clinicians rely on reference databases such as the 1000 Genomes Project, OMIM and others to establish the clinical relevancy. Equally, it’s important for a lab to establish a database of past findings. It’s very likely that a lab with a focus on a particular disease category or a subset of a population has access to variant frequencies specific to the cross section of the community it is serving. Or, it might observe associations between variants and observed phenotypes for diseases that are not yet documented in standard public databases.

Reporting of Incidental Genetic Findings

Clinically significant genetic findings that are unrelated to the phenotype under investigation can occur when performing single gene, gene panel, whole exome or genome sequence analysis. However, limiting sequence analysis to a panel of genes that are relevant to the diagnosis of a particular disease state, for the most part, eliminates the potential for incidental findings. Without question, the analysis of exomes or genomes has a high chance for such findings which include the identification of variants relevant to autosomal dominant disease, carrier status for recessive diseases, predisposition to adult-onset dominant conditions (including cancer and neurodegenerative conditions) and drug response alleles, commonly known as pharmacogenetic markers.

Laboratories considering the use of NGS for clinical testing should be aware of the potential for finding incidental, clinically significant results. Consequently, for those laboratories, it is advisable to have a policy in place for whether and how these results will be reported for those assays where such incidental findings are expected. The ACMG recommendations for reporting medically actionable incidental findings include a minimum gene list for which, if a known mutation is found, it should be reported. Please read further in this paper from Robert Green et al. The included table has the complete list of currently recommended variations to be reported.

It goes without saying that laboratories may also develop their own policies regarding the return of incidental results. For example, if the laboratory’s policy is not to report incidental findings, it should clearly state this fact in the laboratory report.

The reporting of incidental findings opens up a wide range of ethical questions. The level of risk associated with disclosing incidental findings depends on a number of factors such as:

  • Severity of the disease
  • Clinical actionability
  • Level of scientific understanding regarding the observed variations

For example, common disease risk alleles (e.g. for type 2 diabetes or cardiovascular disease) have a low risk to actually materialize. Pharmacogenetic risk information typically has different severities of consequence compared to genetic information indicating a predisposition to cancer (such as Lynch Disease) or other Mendelian disorders, which might have no clinically established treatment options.


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