• The following evidence types are included in this review:

    Previous observations of the variant in individuals
    The type of sequence change and the mechanism of disease
    Experimental evidence
    Indirect and predictive evidence
    Clinical interpretations from other laboratories (variant classifications from other laboratories are noted but are not considered to be independent pieces of evidence)

  • Variant Classification

    After the relevant information has been gathered and the variant has been thoroughly researched, a formal variant classification is assigned following ACMG suggestions.

    A formal classification is meant to help answer two questions about the clinical significance of the sequence change.

    From a diagnostic perspective: Does this sequence change, in the correct genetic background, provide an explanation for disease in an affected individual?

    From a predictive perspective, narrowly applied to highly penetrant conditions: Is an individual who inherits this sequence change likely to develop disease?

The ACMG has recommended a five-tier classification system. According to this system, a sequence change can be classified as:

  • Pathogenic

    This sequence change directly contributes to the development of disease. Some pathogenic sequence changes may not be fully penetrant. In the case of recessive or X-linked conditions, a single pathogenic sequence change may not be sufficient to cause disease on its own. Additional evidence is not expected to alter the classification of this sequence change.

  • Likely Pathogenic

    This sequence change is very likely to contribute to the development of disease; however, the scientific evidence is currently insufficient to prove this conclusively. Additional evidence is expected to confirm this assertion of pathogenicity, but we cannot fully rule out the possibility that new evidence may demonstrate that this sequence change has little or no clinical significance.

  • Uncertain Significance

    There is not enough information at this time to support a more definitive classification of this sequence change.

  • Likely Benign

    This sequence change is not expected to have a major effect on disease; however, the scientific evidence is currently insufficient to prove this conclusively. Additional evidence is expected to confirm this assertion, but we cannot fully rule out the possibility that new evidence may demonstrate that this sequence change can contribute to disease.

  • Benign

    This variant does not cause disease.

Variants are assigned a formal classification based on:

  • Weighted evidence

    The evidence gathered during variant review is scored based on the relative importance of the evidence type. Certain types of evidence may support a pathogenic classification while others may support a benign classification.

  • Grouping by basic argument

    If multiple pieces of evidence point to the same basic argument, only the strongest piece of evidence is considered.

    Example: A functional study that demonstrates reduced protein levels and an in silico algorithm that predicts that the variant is deleterious, both contribute to the general argument that “protein function may be disrupted.”

  • Additive vs. non-additive evidence

    Certain types of evidence can be considered more than once, and certain types cannot.

    Example: Independent observations of the variant in multiple affected individuals are additive.
    Example: Multiple experimental studies demonstrating that different aspects of protein function are disrupted are non-additive.

  • Extensive review to ensure accurate and consistent classification

    Each variant classification undergoes extensive review by our clinical reporting team. Artemis DNA® uses proprietary software tools to efficiently record and share information, an important step to ensure reproducibility for the same variant when evaluated in the future.

  • Reporting

    Highlights the most important findings for your patient
    Provides relevant clinical information about the diseases associated with the genes in which variants were identified
    Describes the relevance of the findings for your patient and their family
    Suggests possibilities for follow-up testing
    Describes in detail the evidence and logic supporting each variant interpretation
    Provides recurrence risk information when possible


  • Summary

    A clear statement summarizing the high-level result of the genetic test — positive, negative, or clinically inconclusive

  • Clinical summary

    A description of the relevance of the genetic results to the patient based on their clinical and family history

  • Complete results table

    A table of the genes in which genetic variants were identified and a complete list of all genes analyzed in the test*

  • Variant details

    A summary of the evidence and logic used to justify the interpretation of each variant

  • Methods and limitations

    A description of Artemis DNA®’ next-generation sequencing assay along with assay limitations

  • The field of genetics is constantly evolving

    The field of genetics is constantly evolving, often revealing new evidence relevant to variant interpretation. When new evidence on a variant becomes available, we review our variant interpretation and, if indicated, we will reclassify the variant and issue an amended report to the ordering clinician. If a report is amended, the ordering clinician will receive a notification via phone or email.

    Genetic testing can have health implications not only for an individual, but for an entire family. Artemis DNA® recommends family variant testing at no additional charge for all first-degree relatives of patients who undergo gene or panel testing for a hereditary condition at Artemis DNA® and are found to have a pathogenic or likely pathogenic variant.

    *Benign variants and silent and intronic variants with no evidence towards pathogenicity are not included in the report but are available upon request.