2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Exploring the Effects of a Point Mutation in the 5' UTR of <em>APC </em>Found in a Family with Colon Cancer

Exploring the Effects of a Point Mutation in the 5' UTR of APC Found in a Family with Colon Cancer

Pdf Summary

A study explored the effects of a point mutation in the 5' UTR of the APC gene in a family with colon cancer. The mutation (-40G>A) was found to potentially create a premature start codon. Computational analysis using PreTIS identified this mutation to have the highest confidence score for aberrant start codon initiation. Luciferase assays confirmed that the presence of the mutation decreased the use of the canonical start codon and that the mutation itself could act as a strong start codon. Co-segregation analysis showed odds of 245:1 in favor of pathogenicity. The variant was not found in the gnomAD database, and the two affected cousins did not share any other potentially pathogenic variants. The study concludes that the mutation qualifies as a likely pathogenic variant based on fulfilling several ACMG criteria, including functional evidence, absence from population databases, and co-segregation analysis. The APC gene is commonly mutated in colorectal cancer and is a high-risk cancer susceptibility gene associated with familial adenomatous polyposis (FAP). If left untreated, FAP can progress to colon cancer. Overall, the study provides evidence supporting the reclassification of the -40G>A variant as likely pathogenic.

Asset Subtitle

Presenting Author - Brendon Young, none; Co-Author - Sean V. Tavtigian, PhD; Co-Author - Kathleen Clark, PhD; Co-Author - Megan B. Keener, BS; Co-Author - Deborah W. Neklason, PhD; Co-Author - Austin Wood, BS; Co-Author - Wendy McKinnon, MSc; Co-Author - Marc S. Greenblatt, MD;

Meta Tag

Phenotype

Sequencing

Co-Author Sean V. Tavtigian, PhD

Co-Author Kathleen Clark, PhD

Co-Author Megan B. Keener, BS

Co-Author Deborah W. Neklason, PhD

Co-Author Austin Wood, BS

Co-Author Wendy McKinnon, MSc

Co-Author Marc S. Greenblatt, MD

Presenting Author Brendon Young, none

Keywords

point mutation

5' UTR

APC gene

colon cancer

aberrant start codon

Luciferase assays

co-segregation analysis

pathogenicity

ACMG criteria

likely pathogenic