The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023

Area of Science:

• Genomics
• Medical Genetics
• Bioinformatics

Background:

• Next-generation sequencing (NGS) generates vast genomic data, posing challenges for genetic disease diagnosis.
• Standardized variant interpretation guidelines are crucial, as established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
• This manuscript details updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, integrating recommendations from major genetics societies and the ClinGen initiative.

Purpose of the Study:

• To establish updated, evidence-based standards for constitutional sequence variant classification.
• To adapt and refine variant classification practices for the Brazilian population.
• To enhance the reliability and uniformity of genetic variant interpretation.

Main Methods:

• Standardized scientific publications and reliable sources for an evidence-based approach.
• Defined databases for variant information, molecular terminology, disease-gene associations, and nomenclature.
• Established general rules for variant classification and Bayesian statistical reasoning principles.
• Implemented bioinformatics standards for automated classification and adhered to ClinGen Variant Curation Expert Panel workflows.
• Developed specific criteria modulation for cancer genes.

Main Results:

• Developed standardized protocols for constitutional sequence variant classification.
• Integrated evidence-based data sources and defined clear classification criteria.
• Established bioinformatics standards for automated variant classification.
• Adapted guidelines for cancer genes and specific considerations for the Brazilian population.

Conclusions:

• The updated standards provide a robust framework for constitutional sequence variant classification.
• These standards, adapted for the Brazilian population, contribute to refining variant classification practices.
• The efforts aim to significantly enhance the reliability and uniformity of genetic variant interpretation.