2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Investigating Independence of PS3 and PM1 Evidence Categories Using Case-Control Data in BRCA1

Pdf Summary

This study investigated the independence of evidence criteria for classifying rare genetic mutations in the BRCA1 gene. Functional assays and computational tools are commonly used to determine the pathogenicity of these mutations. However, failing to consider the effects of one evidence criterion, called PM1, during functional assay calibration can lead to an overestimation of evidence supporting pathogenicity. <br /><br />The researchers constructed a deep multiple sequence alignment for the BRCA1 gene and intersected sequencing data with functional assay data. They stratified the mutations based on the results of the functional assays and the conservation level from the alignment. They then computed frequentist odds ratios to determine the relationship between the evidence criteria.<br /><br />The results showed that there were 16 invariant positions in the RING/BRCT domain of the BRCA1 gene. Variants classified as non-functional and located at canonical residues (specific positions in the gene) had a higher odds ratio than variants classified as non-functional but not located at canonical residues. This suggests that the evidence criteria PM1 and PS3 are not independent of each other.<br /><br />The study suggests that calibration of functional assays should take into account the effects of PM1. Failing to do so may result in an overestimation of evidence supporting pathogenicity from functional assays. This finding highlights the importance of considering all relevant evidence criteria and avoiding inappropriate classification of genetic mutations.

Asset Subtitle

Presenting Author - Scott Pew, MPH; Co-Author - Madison C. Baugh, BS; Co-Author - Julie L. Boyle, MS; Co-Author - David Goldgar, PhD; Co-Author - Sean V. Tavtigian, PhD;

Meta Tag

Cancer Syndromes

Genetic Testing

Policy Issues

Population Genetics

Risk Assessment

Co-Author Madison C. Baugh, BS

Co-Author Julie L. Boyle, MS

Co-Author David Goldgar, PhD

Co-Author Sean V. Tavtigian, PhD

Presenting Author Scott Pew, MPH

Keywords

evidence criteria

genetic mutations

BRCA1 gene

functional assays

computational tools

pathogenicity

PM1

functional assay calibration

sequence alignment

canonical residues