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
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.
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:
Variant classifications from other laboratories are noted but are not considered to be independent pieces of evidence.
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:
Two additional classifications are also periodically invoked to capture variable expressivity:
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.
Our clinical report:
The report includes:
*Benign variants and silent and intronic variants with no evidence towards pathogenicity are not included in the report but are available upon request.
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.
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.