Accurate, clear, and open variant interpretations

Our team of genetic experts works together to turn data into meaning

Invitae’s method of variant classification

Invitae’s variant classifications are based on a rigorous, logical, and reproducible assessment of available evidence. We aim to be comprehensive in our review of the available literature and evidence, transparent in our logic and our conclusions, and clear in our explanations.

Our systematic process captures, assesses, and categorizes the evidence on a genetic variant, then applies a formal classification based on this evidence.
 This method adheres closely to the recommendations from the American College of Medical Genetics (ACMG) and represents the industry standard among clinical genetic testing laboratories.

We published this process in Genetics in Medicine, the official, peer-reviewed journal of ACMG. The paper describes our method in great detail, without copyright or intellectual property claims. We encourage other laboratories to also use reproducible, transparent methods in their variant classification, and even apply our system if desired.

Invitae's variant interpretation process is described below. To learn more details, read the Genetics in Medicine paper, download our white paper, review our 2015 ACMG poster, or watch our recorded webinar on this topic.

Read the Genetics in Medicine paper — Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Download white paper — Invitae's method of variant classification Download ACMG 2015 poster — Sherloc: A weighted, score-based variant classification system based on the 2015 ACMG ISV guidelines Watch recorded webinar

A team of genetic experts

At Invitae, scientists, genetic counselors, and medical geneticists work as a team to provide high-quality and rigorous variant interpretations, then describe how these findings relate to your patient’s clinical situation.

Unusual and/or complicated variants are discussed at a regular case review conference. The entire process is supported by proprietary software that ensures the work is comprehensive, reproducible, consistent, and efficient.

Interpretation and reporting process

1

Variant research

The first step of variant interpretation is collecting and evaluating all available evidence related to the variants identified in the patient’s data. We are up-to-date in our monitoring of the peer-reviewed literature and critically evaluate the evidence presented in that literature. We perform a comprehensive evaluation of population and locus-specific databases, and carefully apply information from in-silico predictors. We are systematic in our categorization and weighing of the evidence.

The following evidence types are included in this review:

  • Previous observations of the variant in individuals
  • The type of variant and the mechanism of disease
  • Experimental evidence
  • Indirect and predictive evidence

Variant classifications from other laboratories are noted but are not considered to be independent pieces of evidence.

2

Variant classification

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

Invitae approaches variant classification from a strict Mendelian perspective and employs the recommended five-tier classification system recommended by ACMG. A sequence change can be classified as:

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

  • Likely pathogenic — This variant 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 variant has little or no clinical significance.
  • Uncertain significance — There is not enough information at this time to support a more definitive classification of this variant.
  • Likely benign — This variant 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 variant can contribute to disease.
  • Benign — This variant does not cause disease.

Two additional classifications are also periodically invoked to capture variable expressivity:

  • Pathogenic (low penetrance) — This variant is commonly accepted as a contributing factor of disease, but the penetrance of this particular change is sufficiently low (<25%) to be often seen in individuals without disease. As a result, the predictive value of this information is considered to be low.
  • Pseudodeficiency allele — This variant can lead to false positive results on biochemical enzyme studies, but is not known to cause clinical symptoms or lead to disease. Enzyme studies cannot differentiate between true pathogenic variants and pseudodeficiency alleles, so these must be distinguished by molecular studies.

3

Reporting

Our clinical report:

  • 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

The report includes:

  • 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 Invitae's next-generation sequencing assay along with assay limitations

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

Amended reports

When new evidence on a variant becomes available, we review our variant interpretation. If indicated, we will reclassify the variant, then issue an amended report to the ordering clinician. If a report is amended, the ordering clinician will receive a notification, either by phone call or by email.

Family testing services

Genetic testing can have health implications — not only for an individual, but for an entire family. To help resolve variants of uncertain significance (VUS) in our test results, Invitae offers complimentary follow-up testing to select family members of patients tested at Invitae if an Invitae lab director determines that doing so will aid in variant interpretation. We also offer affordable family variant testing to enable identification of other family members who have the same variant as the original patient.

To learn more about these programs, please visit our VUS Resolution and Family Variant Testing pages.