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Catalog
2023 ACMG Annual Clinical Genetics Meeting Digital ...
Functional Analysis Provides Insight into Missing ...
Functional Analysis Provides Insight into Missing Heritability
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Functional analysis was conducted to gain insight into the missing heritability associated with ATM variants in a high-risk cohort. The homology directed repair (HDR) assay and the radiomimetic bleomycin were used to assess DNA repair efficacy. Variants were found to have reduced activity in HDR and showed early hypersensitivity in key variants. Mechanistic exploration using western blotting was done to analyze phosphorylation of specific targets downstream of ATM. Several variants exhibited defects in function, with V2540I performing similar to negative controls in all assays. The C-Terminal BRCA2 variant K3326X was also studied, as it had a controversial interpretation of pathogenicity. The findings from multiple cohort studies regarding this variant were summarized. Various hypotheses were presented regarding the impairment of BRCA2 activity conferred by K3326X. The study of ATM variants in patients with familial cancer patterns aimed to address the knowledge gap in genetic risk prediction. Detailed biochemical studies were conducted on selected missense mutations to improve variant risk assessment. The findings and recommendations for each variant were listed. The laboratory's novel approach involved identifying variants of unknown significance (VUS) in a high-risk patient cohort and subjecting them to computational analysis and detailed laboratory studies. Previous studies by the lab examined a cohort of women with ovarian cancer and identified high-risk variants in DNA repair and cell cycle control genes. In silico analysis and subsequent laboratory studies were performed to assess the pathogenicity of these variants. Selected references for further reading on ATM and BRCA2 were provided.
Asset Subtitle
Presenting Author - Scott Baughan, BS; Co-Author - Michael A. Tainsky, PhD; Co-Author - Fatima Darwiche, MS;
Meta Tag
Clinical History
Counseling
Genetic Testing
Pathogenesis
Polymorphism
Risk Assessment
Sequencing
Susceptibility Locus
Variant Detection
Co-Author
Michael A. Tainsky, PhD
Co-Author
Fatima Darwiche, MS
Presenting Author
Scott Baughan, BS
Keywords
functional analysis
ATM variants
DNA repair efficacy
variants activity
C-Terminal BRCA2 variant
K3326X
BRCA2 impairment
genetic risk prediction
missense mutations
variant risk assessment
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