nihms697486

Standards and Guidelines Overview

Title: Standards and Guidelines for the Interpretation of Sequence Variants

Authors: Joint consensus recommendation by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP).

Contributors

  • Sue Richards (ACMG), Oregon Health & Science University, Portland, OR, USA

  • Nazneen Aziz (CAP), Phoenix Children’s Hospital, USA

  • Sherri Bale (ACMG), GeneDx, Gaithersburg, MD, USA

  • David Bick (ACMG), Medical College of Wisconsin, Milwaukee, WI, USA

  • Soma Das (ACMG), The University of Chicago, USA

  • Julie Gastier-Foster (AMP), Nationwide Children's Hospital, Columbus, OH, USA

  • Wayne Grody (ACMG), UCLA, Los Angeles, CA, USA

  • Elaine Lyon (AMP), University of Utah, Salt Lake City, UT, USA

  • Karl Voelkerding (CAP), University of Utah, Salt Lake City, UT, USA

  • Heidi L. Rehm (ACMG), Brigham & Women’s Hospital, Boston, Massachusetts, USA

Introduction

The ACMG has historically developed guidelines for interpreting sequence variants, aiming to enhance the consistency and accuracy of genetic analysis. Over the past decade, there have been rapid advancements in sequencing technologies, notably next-generation sequencing (NGS), which have revolutionized genetic testing by increasing throughput and enabling comprehensive genome analysis. However, this evolution has also introduced significant complexity in understanding and interpreting genetic variants, requiring a reevaluation of standards.

In response to these challenges, the ACMG, in collaboration with AMP and other associated organizations, undertook a thorough review of the existing guidelines and adjusted the recommendations to reflect new knowledge and practices in the field. This iteration focuses on critical areas where guidance is most pertinent and where misinterpretation could lead to adverse clinical outcomes.

Recommendation Overview

The updated recommendations encompass a wide array of genetic tests, including genotyping, single gene evaluations, gene panels, whole exome sequencing, and whole genome sequencing. A standard terminology is proposed to facilitate clearer communication regarding the classification of genetic variants:

  • Pathogenic: Variants known to cause disease.

  • Likely pathogenic: Variants with strong evidence indicating potential disease causation but lacking full confirmation.

  • Uncertain significance: Variants for which the impact is unclear and requires further investigation.

  • Likely benign: Variants that are unlikely to affect health based on existing evidence.

  • Benign: Variants known not to cause disease.

Variant classification must incorporate a comprehensive range of evidence types, including population data, computational predictions, functional studies, and family segregation analyses.

Importance of Adherence to Standards

While adherence to these guidelines is promoted, it is essential to understand that it remains voluntary and does not guarantee successful medical outcomes. Clinical laboratory geneticists are urged to exercise their professional judgment and document the rationale for their decisions in patient records. This documentation supports transparency and clinical diligence.

Workgroup Formation and Process

Established in 2013, a diverse workgroup comprising representatives from ACMG, AMP, and CAP was tasked with compiling and revising evidence criteria. The workgroup initiated surveys aimed at identifying best practices for variant evaluation and classification, prioritizing rigorous input from clinical practitioners. Their findings were presented at the ACMG annual meeting and influenced further refinements based on laboratory stakeholder feedback. This collaborative process is crucial for addressing the realities faced in laboratory settings.

General Considerations in Variant Interpretation

To encourage clarity, the guidelines recommend the use of the term "variant" in place of outdated terms like “mutation” and “polymorphism,” supplemented with specific modifiers for added clarity. Assertions regarding the pathogenicity of variants must be context-sensitive, taking into account the individual’s condition, family history, and inheritance patterns. Moreover, laboratories may adopt additional internal classification tiers tailored to their specific operational needs.

Nomenclature and Reporting Standards

Uniform nomenclature is vital for the effective use of genomic information. The Human Genome Variation Society (HGVS) provides comprehensive guidelines for consistent variant naming. Reports generated should clearly articulate variant classifications, specifying associated genetic information including gene name, disease context, inheritance patterns, and classification status.

Use of Databases and Literature in Variant Assessment

When assessing the pathogenicity of variants, population databases should be leveraged judiciously to evaluate allele frequencies, although users are cautioned to ensure the credibility and verification of the data sources being utilized. A careful review of scientific literature is imperative to avoid misinterpretation due to outdated nomenclature.

Computational Predictive Programs

The report outlines various computational predictive tools that assist in determining the potential impact of identified sequence variants. However, it emphasizes that these predictions should not be the exclusive basis for clinical decisions regarding variant pathogenicity.

Proposed Criteria for Evaluating Variants

The guiding report establishes a robust framework for the classification of genetic variants based on accrued evidence. Distinguishing between pathogenic and benign variants is particularly crucial in clinical environments where interventions may significantly impact patient health.

Variant Classification Evidence Framework

  • Strong evidence for pathogenicity includes instances such as null variants in known disease-causing genes.

  • Moderate evidence encompasses de novo variants as well as those located in well-documented mutational hotspots.

  • Benign evidence may involve variants that exhibit high allele frequencies in general population databases or are present in unaffected individuals not displaying disease symptoms.

Summary of Best Practices for Reporting and Interpretation

Clinical reports should be designed to be clear, straightforward, and informative for both healthcare providers and patients. They should also provide actionable recommendations for follow-up tests and additional clinical evaluations where warranted. Encouragement of collaboration between laboratories and healthcare providers can enhance patient management and outreach based on genetic findings. Regular updates and re-evaluations of variant classifications are essential in light of emerging data and evolving understandings of genetics.

Special Considerations on Variant Usage

Caution is advised when interpreting variants, particularly in the context of benign findings and among asymptomatic individuals. Special care must be taken regarding mitochondrial variants and those involved in pharmacogenomics, due to their unique complexities and the potential implications for patient treatment strategies.

Conclusion

These consistent guidelines are designed to support clinical laboratories by ensuring quality and precision in genetic testing practices. The emphasis on the necessity of professional judgment and a thorough evaluation of evidence plays a pivotal role in the accurate interpretation of genetic variants, ultimately aiding in effective clinical decision-making.