MutationAssessor in cBioPortal

Area of Science:

• Genomics
• Bioinformatics
• Computational Biology

Background:

• Somatic and germline mutations in cancer require functional impact assessment.
• MutationAssessor (MA) provides an evolution-based functional impact score (FIS) for mutations.
• FIS scores leverage conservation patterns in protein families and subfamilies.

Purpose of the Study:

• To introduce version 4 (r4) of MutationAssessor with significant improvements.
• To refine the analysis of protein conservation patterns and sequence alignments.
• To validate predicted functional impacts against curated variant databases and germline frequencies.

Main Methods:

• Refined combinatorial entropy analysis of conservation patterns.
• Recalculated full-length protein multiple sequence alignments using extensive sequence data.
• Comparison of predicted functional impact with ClinVar classifications.
• Analysis of variant frequency in germline genome sequences.
• Exploration of switch-of-function mutational effects.

Main Results:

• Enhanced accuracy in predicting the functional impact of cancer mutations.
• Validation of FIS scores against known pathogenic and benign variants.
• Observed inverse correlation between high functional impact and germline variant frequency.
• Availability of functional impact data for ~4 million somatic mutations in cBioPortal.

Conclusions:

• MutationAssessor r4 offers a robust tool for evaluating the functional consequences of cancer mutations.
• The updated FIS provides valuable insights into mutation pathogenicity and evolutionary conservation.
• The integration of MA data into cBioPortal facilitates cancer genomics research and clinical interpretation.