Predictive functional assay-based classification of PMS2 variants in Lynch syndrome

Area of Science:

• Genetics and Genomics
• Cancer Predisposition Syndromes
• Molecular Diagnostics

Background:

• Germline alterations in the DNA mismatch repair (MMR) gene PMS2 are associated with Lynch syndrome, a cancer predisposition.
• A majority of identified PMS2 variants are classified as variants of uncertain significance (VUS), hindering clinical management.
• Accurate VUS classification is crucial for personalized cancer risk assessment and genetic counseling.

Purpose of the Study:

• To develop a quantitative tool for classifying VUS in the PMS2 gene.
• To establish a formula translating functional assay results into pathogenicity odds for PMS2 VUS.
• To improve the clinical interpretation of PMS2 variants for Lynch syndrome risk.

Main Methods:

• Utilized the complete in vitro MMR activity (CIMRA) assay for functional analysis of PMS2 VUS.
• Developed the OddsPath formula integrating CIMRA results with clinically classified and experimentally generated PMS2 variants.
• Validated the predictive accuracy of the OddsPath formula for both benign and pathogenic PMS2 VUS.

Main Results:

• The OddsPath formula demonstrated high predictive values for classifying PMS2 VUS.
• The CIMRA assay provides a quantitative, sequence-based method for VUS assessment.
• The OddsPath metric effectively distinguishes between benign and cancer-predisposing PMS2 VUS.

Conclusions:

• The OddsPath metric offers a robust tool for PMS2 VUS classification, complementing existing methods.
• This approach can be integrated as strong evidence into upcoming ACMG/AMP guidelines for MMR gene VUS.
• Improved VUS classification for PMS2 will enhance personalized healthcare for Lynch syndrome patients.