Related Experiment Video

Updated: Jul 23, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.7K

Actionability classification of variants of unknown significance correlates with functional effect

Amber Johnson1, Patrick Kwok-Shing Ng1, Michael Kahle1

  • 1Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

NPJ Precision Oncology
|July 15, 2023
PubMed

Insights

Classifying variants of unknown significance (VUS) using the Precision Oncology Decision Support (PODS) system helps identify potentially actionable genomic alterations. This approach aids in selecting patients for targeted cancer therapies.

Area of Science:

  • Oncology
  • Genomics
  • Bioinformatics

Background:

  • Genomic alterations guide cancer therapy, but many variants of unknown significance (VUS) lack clear clinical implications.
  • Accurate interpretation of VUS is crucial for precision oncology.

Purpose of the Study:

  • To evaluate a rule-based classification system for VUS actionability.
  • To compare this classification with functional genomics data.

Main Methods:

  • The Precision Oncology Decision Support (PODS) team classified VUS based on location within functional domains or proximity to known oncogenic variants.
  • A functional genomics platform (mutant generation, cell viability assays) was used to validate the PODS classification.
  • 438 VUS in 20 actionable genes were analyzed.

Main Results:

  • 106 (24%) of VUS were confirmed as oncogenic by functional assays.
  • VUS classified as 'Potentially' actionable by PODS (37%) were significantly more likely to be oncogenic than those classified as 'Unknown' (13%).
  • A statistically significant difference (p=4.08e-09) was observed between the two classifications.

Conclusions:

  • Rule-based actionability classification of VUS is a valuable tool.
  • This method can help identify patients with actionable variants for genomically-matched therapy.

More Related Videos

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

11.0K
Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA11:35

Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA

Published on: August 21, 2016

13.0K

Related Concept Videos

Mutations01:39

Mutations

Overview
83.8K
Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
40.6K
Genome-wide Association Studies-GWAS01:11

Genome-wide Association Studies-GWAS

Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
13.6K
Mutagenicity and Carcinogenicity01:25

Mutagenicity and Carcinogenicity

Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
1.3K
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
9.0K
Comparing Copy Number Variations and SNPs02:26

Comparing Copy Number Variations and SNPs

Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
17.8K