2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Comprehensive Functional Analysis of CHEK2 Variants: A Novel Approach to Classify Hereditary Cancer Syndrome Variants of Uncertain Significance

Comprehensive Functional Analysis of CHEK2 Variants: A Novel Approach to Classify Hereditary Cancer Syndrome Variants of Uncertain Significance

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A study conducted by researchers from Wayne State University School of Medicine aimed to classify variants of uncertain significance (VUSs) in the CHEK2 gene, which is associated with hereditary cancer syndromes. The researchers used error-prone PCR to generate random mutations in the CHEK2 gene and performed a functional screen using yeast to identify variants with impaired function. They then sequenced the isolated variants to identify enriched or depleted amino acid variants. The study established a method to comprehensively analyze the functional consequences of single nucleotide variants throughout the CHEK2 gene.<br /><br />The functional screen predicted the functional impact of 3,187 out of 3,188 non-synonymous amino acid changes in the CHEK2 gene with 98% accuracy, including all VUSs. The study also compared the functional predictions of the screen to in silico prediction tools and found differences in some variants classified as VUSs.<br /><br />The researchers concluded that comprehensive functional analyses of VUSs can lead to more accurate variant annotations and improve genetic counseling and patient care. They also mentioned plans to replicate the functional screen using mammalian cells and apply the analysis method to other cancer-causing genes in the DNA repair pathway.<br /><br />Overall, the study provides valuable insights into the classification of VUSs in the CHEK2 gene and highlights the importance of functional analysis in interpreting genetic data. The findings have the potential to expand the diagnostic impact of genetic testing and improve treatment for hereditary cancer syndromes.

Asset Subtitle

Presenting Author - Claire Mccarthy-Leo, MS, ASCP(MLS)CM; Co-Author - George Brush, PhD; Co-Author - Michael A. Tainsky, PhD; Co-Author - Russel L. Finley, PhD;

Meta Tag

Cancer Syndromes

Risk Assessment

Sequencing

Structure/Function

Co-Author George Brush, PhD

Co-Author Michael A. Tainsky, PhD

Co-Author Russel L. Finley, PhD

Presenting Author Claire Mccarthy-Leo, MS, ASCP(MLS)CM

Keywords

CHEK2 gene

variants of uncertain significance

hereditary cancer syndromes

error-prone PCR

functional screen

yeast

amino acid variants

single nucleotide variants

in silico prediction tools

genetic counseling