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Quest Diagnostics

Variant investigation

The team: Variant IQ™

Variant IQ™ is a team of highly specialized and rigorously trained scientists and genetic counselors whose primary focus is to assess the pathogenicity of genetic variants identified in patients. We strive to provide the best service for our customers by staying up-to-date with the latest advances in genetics, which includes decades of internal data accumulated within our in-house database of variants previously identified. We stay updated with these advances by attending conferences, presenting research, and sustaining collaborations, such as participation in Clingen working groups and partnerships with academia. 

Publications and presentations by the variant science team

What is variant science?

Variant science is a field of genetics focused on identifying and interpreting variants in DNA to understand their effect on human health. Variants, sometimes referred to as mutations, are differences in the DNA sequence compared to the reference genome sequence, or what is most commonly seen in the general population. Most variants are harmless and reflect normal genetic diversity, while others can influence how genes function and may contribute to disease. Variant IQ™ evaluates variants found in the human genome, specifically from germline or somatic cell samples. Through this analysis, we can help better understand how your genetic results may have an impact on your health.

We evaluate two main types of genetic variants: single nucleotide variants (SNVs) and copy number variants (CNVs). SNVs are small changes in the DNA sequence where a single building block (nucleotide) is altered. These changes take several forms, including silent variants, where the change does not affect the protein coding sequence; missense variants, where the change leads to a change in the amino acid sequence; and truncating variants, where the change leads to the partial or complete loss of protein production. CNVs, on the other hand, involve larger changes where segments of the DNA are either duplicated or deleted, affecting the number of copies of certain genes. These types of variants can be associated with a wide range of genetic conditions, from developmental disorders to cancers. 

We use several advanced technologies to sequence DNA and identify genomic variants, including next-generation Sequencing (NGS), Sanger sequencing, and array comparative genomic hybridization (aCGH). Next-generation sequencing (NGS) is a high-throughput method that allows for the simultaneous analysis of multiple genes, making it ideal for detecting SNVs and small insertions or deletions. Sanger sequencing, a more traditional and highly accurate technique, is used to confirm NGS findings or to sequence specific regions of the DNA in cases where NGS is not practical. Array comparative genomic hybridization (aCGH) is another widely used technology that detects larger chromosomal changes, such as duplications and deletions. Together, these technologies enable accurate and efficient identification of clinically relevant genetic variants.

Our team utilizes a wide range of curated databases, primary literature, and decades of internal variant information to evaluate relevant gene and variant information. Variant assessment begins with gathering gene-level information to understand the relevance of the gene to a condition. Public databases such as ClinGen and GenCC provide expert-curated evaluations of gene-disease associations, helping determine whether a gene is definitively associated with a particular condition. Similarly, OMIM and MedGen offer comprehensive overviews of gene-disease associations, inheritance patterns, and associated phenotypes. Once a gene is established as relevant, variant-level evaluation relies on additional resources including population databases like gnomAD, DGV, and FLOSSIES, which are used to determine how common a variant is in the general population. ClinVar and Decipher provide valuable insights into how other clinical laboratories have interpreted a variant’s significance, often including supporting evidence and clinical context. We use several public and private databases that offer curated reports of published disease-associated variants and allow for comprehensive literature searches to identify case reports, functional studies, and other relevant data. Additionally, we use tools that make in silico predictions and links to many of the previously described databases. 

Our team actively engages in the community through submissions to public databases and participation in professional committees.

ClinVar participation: Quest Diagnostics submits variant classifications to ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/intro/, a public NIH database, in accordance with Clinical Genome Resource (ClinGen) requirements to support quality of care. For patients who are interested in sharing their own deidentified genetic and personal health information to improve understanding of genetics and health, please visit https://GenomeConnect.org. GenomeConnect is an online registry designed by ClinGen that facilitates patients sharing their own deidentified information with ClinVar and is not affiliated with Quest Diagnostics.

ClinGen participation: to see a list of members of our team who volunteer on various working groups and expert panels with ClinGen, please visit https://clinicalgenome.org/about/organizations/quest-diagnostics/

A necessary component of determining variant pathogenicity is first identifying whether there is a relationship between a gene and a specific disease and the strength of that relationship (ie, gene-disease association). This aids in determining whether certain types of evidence can be applied when evaluating variants within the gene. To assess the strength of a gene-disease association, our team's streamlined and standardized process utilizes evidence from primary literature as well as from curated databases, such as ClinGen, and internal data.

 

Published guidelines for our current processes:

A Streamlined Process for Assessing the Strength of a Relationship Between a Gene and Specific Disease

To assess the pathogenicity of genetic variants in patients, we use a rules-based process aligned with the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines, integrating published research with data from our internal knowledge base, external databases, engagement in professional society collaborations, and clinician-provided phenotypes. Close collaboration among our scientists, genetic counselors, clinical laboratory directors, and pathologists ensures that all the relevant information has been collected and systematically analyzed to provide the most clinically informative result to our clients.

Published guidelines our current process is aligned with: 

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders

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

To assess the pathogenicity of genetic variants in patients, we use a rules-based process aligned with the American College of Medical Genetics (ACMG) guidelines, integrating published research with data from our internal knowledgebase, external databases, engagement in professional society collaborations, and clinician-provided phenotypes. Close collaboration among our scientists, genetic counselors, and clinical laboratory directors ensures that all the relevant information has been collected and systematically analyzed to provide the most clinically informative result to our clients. 

Published guidelines aligned with our current process:

Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)

Somatic tiering is a classification system for somatic variants to further determine their clinical actionability. To assess the tier of a somatic variant, we use predictive/therapeutic, diagnostic, and prognostic evidence. This tiering system takes into account the clinical actionability of a somatic variant within a specific cancer type and whether there is an associated drug treatment. These guidelines are aligned with a joint consensus of recommendations from AMP/ASCO/CAP.  This is a four-tiered system with the top two tiers being subdivided into categories based on levels of evidence applied. The tiers are as follows:

  • Tier 1, Level A: Variants of Strong Clinical Significance (Includes biomarkers that predict response or resistance to FDA-approved therapies for a specific type of tumor, or biomarkers that are included in professional guidelines as diagnostic/prognostic/predictive of response or resistance to therapies for a specific type of tumor.)

  • Tier 1, Level B: Variants of Strong Clinical Significance (Includes biomarkers that are diagnostic/prognostic/predictive of response or resistance to therapies for a specific type of tumor based on well-powered studies with consensus from experts in the field.)

  • Tier 2, Level C: Variants of Potential Clinical Significance (Includes biomarkers that predict response or resistance to therapies approved by the FDA or professional societies for a different type of tumor, or biomarkers that serve as inclusion criteria for clinical trials, or biomarkers of  diagnostic/prognostic significance based on the results of multiple small studies.)

  • Tier 2, Level D: Variants of Potential Clinical Significance (Includes biomarkers that show plausible therapeutic significance based on preclinical studies, or biomarkers that may assist disease diagnosis/prognosis themselves or along with other biomarkers based on small studies or a few case reports.)

  • Tier 3: Variants of Unknown Clinical Significance (Includes alterations not observed at a significant allele frequency in the general or specific subpopulation databases or pan-cancer or tumor-specific variant databases; no convincing published evidence of cancer association.)

  • Tier 4: Benign or Likely Benign Variants (Includes alterations observed at significant allele frequency in the general or specific subpopulation databases; no existing published evidence of cancer association.)

 

Published guidelines aligned with our current process:

Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer

Variant classification definitions

A variant that has strong scientific and clinical evidence showing it causes or increases the risk of developing a disease may be classified as "likely pathogenic" or "pathogenic," depending on the strength of the available data.

A variant whose clinical significance is uncertain based on current data or the lack of data may be classified as a "variant of uncertain significance (VUS)." 

Additionally, within variants of uncertain signficance there can be a subclassification given. These subclassifications aid in indicating if the variant is leaning toward benign or pathogenic. These subclassifications are only used for single nucleotide variants (SNVs). 

A variant that may increase an individual's risk of developing a disease may be classified as a "risk allele." Risk alleles are typically low penetrance and may have additional complexities that are not typically observed in Mendelian genetics.

A variant that has evidence suggesting it does not cause disease or increase the risk of developing a disease may be classified as "likely benign" or "benign," depending on the strength of the available data.

Family Insight Program (FIP)

The Family Insight Program (FIP) is a no-cost testing service for eligible family members of individuals who have received a variant of uncertain significance (VUS) result. This service is available for select genetic tests when additional family testing may help clarify a variant's clinical significance. The tests eligible for this program include sequencing panels and chromosome microarray.

To perform this testing, certain criteria must be met, which include the variant meeting a specific threshold of specificity, a detailed family history, submission of a detailed patient clinical information, completion of HIPAA forms from family members, consent forms from all individuals involved in the testing, and an application form. We offer this program with the hope of further clarifying the significance of the variant(s).

It is important to note, participation in the Family Insight Program does not guarantee VUS reclassification. Participation of family members in the Family Insight Program should also not replace genetic counseling and/or clinically indicated genetic testing. 
 
Additionally, incidental findings identified through this program will not be evaluated. Identity testing may be performed as a quality measure. Family members that are tested will not receive a report and/or result. At the completion of the program, the initial individual’s report may be updated to incorporate any additional information or reclassification of the patient’s variant. 

Clinicians will be notified, and the patient will receive an addended report. 

The patient’s clinician will be contacted regardless. It is possible new information (external and internal) will become available in the future, which may cause the VUS classification to change. Since we cannot predict if or when this reclassification will occur, it is important for your patient to remain in contact with your office to ensure they can be notified of any change in the interpretation of the VUS.

  • The variant has been classified as benign, likely benign, likely pathogenic, or pathogenic, or if the patient has an otherwise positive report. This may happen if FIP testing occurs years after initial reporting.  

  • The VUS variant is associated with a specific inheritance pattern and/or the variant does not meet a value threshold. In these cases, further family genetic information will not clarify the significance of the VUS.

  • The phenotype of the patient is inconsistent with the reported phenotype of the gene(s) involved.

  • Required family member(s) decline to participate, by either refusing the testing or not sending a sample for testing.   

Variant reevaluation services

Variant reevaluation is the process of investigating new information regarding a variant. Reevaluation can result in reclassification of a variant when new information is taken into account. Reevaluation is typically performed on results from sequencing panels and chromosome microarray results. 

Reevaluation differs from reanalysis; reanalysis is only applicable for exome testing, which involves re-analysis of the exome case as a whole and not just an individual variant.

Variant reevaluation can help provide further evidence to support or oppose a variant's function in disease as new evidence becomes available. This can help clincians determine if they need to do further studies to aid in diagnosing a patient.

We will reevaluate variants that are included in the interpreted reports by Quest Diagnostics. Quest Diagnostics has implemented expiration dates for variant classification. If the classification of the variant you have requested is not expired, the variant may not be applicable for reevaluation. If the clinician has new information such as family history, family genetic testing results, and/or better phenotypic information, we can reevaluate the variant before the expiration date. 

Below is our Contact Us form that the clinician can complete and submit, or call Genomic Client Services at 1.866.436.3463. 

The clinician’s office will be contacted regardless of a change in classification. If the classification does change, a new report can be released upon the request of the clinician or by the rules set forth by the laboratory that performed the service. 

Variant reclassification services

Variants are re-assessed periodically as new information becomes available, which may lead to a change in a variant's classification. 

We will contact the ordering clinician on file with an updated report if a variant has a significant change in classification that may alter the treatment course or allow clinicians to further investigate the genetic cause of disease in the patient. We will contact the ordering clinician and addend the report when applicable. This applies to variants reported in the last 5 years. It is the duty of the ordering clinician to make sure these updated results are communicated to the patient.
 
Clinicians may also proactively contact Quest Diagnostics regarding a change in variant classification using the Contact Us form or by calling Genomic Client Services at 1.866.436.3463. 

Action and Education

To request an update on the classification of a variant, please use the form below.

Only a patient’s treating physician can make diagnoses or prognostic or treatment decisions based on the knowledge of the patient, history, and clinical/educational experience. Quest lab testing provides information for the physician to use in helping make such decisions.

Contact Us online

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The team: Variant IQ™

Publications and presentations by the variant science team

What is variant science?

Family Insight Program (FIP)

Variant reevaluation services 

Variant reclassification services

Action and education

Contact Us online

Our company

Quest® is the brand name used for services offered by Quest Diagnostics Incorporated and its affiliated companies. Quest Diagnostics Incorporated and certain affiliates are CLIA-certified laboratories that provide HIPAA-covered services.  Other affiliates operated under the Quest® brand, such as Quest Consumer Inc., do not provide HIPAA-covered services. 

 

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