Standardisation of pathogenicity classification for somatic alterations in solid tumours and haematologic...

Area of Science:

• Genomic Medicine
• Cancer Genomics
• Clinical Bioinformatics

Background:

• Interpreting somatic alterations becomes challenging with larger sequencing panels.
• Accurate classification of variant pathogenicity is essential for guiding cancer patient management.
• Actionability assessment of somatic variants is critical for therapeutic decisions.

Purpose of the Study:

• To describe a detailed workflow for classifying somatic variant pathogenicity in cancer.
• To establish a standardized approach for interpreting cancer-related genomic alterations.
• To categorize somatic variants into five distinct pathogenicity levels.

Main Methods:

• A classification system combining eight criteria for pathogenic or benign effects was developed.
• Criteria include stand-alone, very strong, strong, moderate, and supporting evidence levels.
• The workflow adapts germline variant interpretation guidelines (ACMG/AMP 2015) for somatic contexts.

Main Results:

• The proposed workflow considers cancer-specific factors: disease context, therapeutic implications, co-occurring genomic events, and gene function (oncogene/tumor suppressor).
• It leverages cancer-specific variant databases for enhanced interpretation accuracy.
• The approach ensures interpretation aligns with established guidelines while addressing somatic variant nuances.

Conclusions:

• The classification workflow aims to standardize best practices for somatic variant pathogenicity interpretation.
• Implementation can improve interpretation consistency within and between molecular diagnostic laboratories.
• Enhanced consistency facilitates more reliable clinical decision-making for cancer patients.