Variant Classification

Receiving a variant of unknown significance (VUS) result from genetic testing can be challenging. We are committed to offering clinicians clear, accurate, clinically-relevant details about a VUS, to help the patients and families impacted by these results.

Ambry's Variant Assessment and Classification scheme helps bring clarity to genetic testing results by providing:

  1. Clinical recommendations for medical management, family member testing, follow-up studies
  2. Comprehensive results reports with a clinical interpretation, available evidence summary, supporting materials
  3. Automatic reclassification alerts to clinicians when a significant variant classification update occurs 
  4. Our active Family Studies Program for VUS testing in informative families

Variants found through genetic testing are currently classified and reported as follows:

  • Pathogenic Mutation: alterations with sufficient evidence to classify as pathogenic (capable of causing disease). Targeted testing of at-risk family members and appropriate changes in medical management (i.e. high risk surveillance) for pathogenic mutation carriers recommended. A pathogenic mutation is always included in results reports.
  • Variant, Likely Pathogenic (VLP): alterations with strong evidence in favor of pathogenicity. Targeted testing of at-risk family members and appropriate changes in medical management (i.e. high risk surveillance) for VLP carriers recommended. A VLP is always included in results reports.
  • Variant, Unknown Significance (VUS): alterations with limited and/or conflicting evidence regarding pathogenicity. Targeted testing of informative family members to collect cosegregation data via our Family Studies Program recommended. Medical management based on personal and family histories, not VUS carrier status. A VUS is always included in results reports.
  • Variant, Likely Benign (VLB): alterations with strong evidence against pathogenicity Targeted testing of at-risk family members not recommended. Medical management based on personal and family histories. A VLB is not routinely included in results reports.
  • Benign: alterations with very strong evidence against pathogenicity. Targeted testing of at-risk family members not recommended. Medical management based on personal and family histories. Benign alterations are not routinely included in results reports.

Family Studies Program

Through our Family Studies Program, informative family members of patients found to carry a VUS are eligible for testing for the same alteration. The co-segregation data from these studies can help clarify the clinical significance of a VUS. Complete review of application materials is required prior to approval of family studies. Please visit our Family Studies Program page for details.

Reclassification Efforts
Our dedicated Ambry Variant Assessment (AVA) team is interdisciplinary and comprised of MD and PhD laboratory directors, biostatisticians/bioinformaticians, structural biologists, variant scientists, and genetic counselors with specialized expertise in subspecialties (e.g. nonsense mediated decay, protein modeling). Our team continuously re-assesses variant data. When enough evidence becomes available to warrant a significant change in a previously-reported classification, reclassification alerts are automatically generated and sent to clinicians. This allows clinicians to be confident that they have the most updated and clinically useful information possible for their patients.
 
Recommended Publications for Further Information
  1. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24.
  2. Caleshu C, et al. Use and interpretation of genetic tests in cardiovascular genetics. Heart. 2010 Oct;96(20):1669-75.
  3. Plon SE, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008 Nov;29(11):1282-91.
  4. Richards CS, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med. 2008 Apr;10(4):294-300.
  5. Spurdle AB, et al. Prediction and assessment of splicing alterations: implications for clinical testing. Hum Mutat. 2008 Nov;29(11):1304-13.
  6. Tavtigian SV, et al. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat. 2008 Nov;29(11):1261-4.
  7. Tavtigian SV, et al. In silico analysis of missense substitutions using sequence-alignment based methods. Hum Mutat. 2008 Nov;29(11):1327-36.
  8. Thompson BA, et al. A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. Hum Mutat. 2013 Jan;34(1):200-9.
  9. Rehm HL, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013 15(9):733-747

Questions or Feedback?
General comments/feedback and specific inquiries about our variant assessment and classification system can be emailed to variantsupport@ambrygen.com