A genetic variant refers to a difference in the DNA sequence among individuals. Variants can occur at single nucleotide positions, larger segments of DNA, or entire chromosomes. They contribute to the genetic diversity within a population and can have various effects on an organism’s traits, including physical characteristics, susceptibility to diseases, and response to medications. There are several types of genetic variants e.g., single nucleotide variants (SNVs). insertions and deletions (Indels), copy number variants (CNVs), and structural variants.
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Types of Genetic Variants
- Benign Variants: These variants have no noticeable impact on health or development.
- Pathogenic Variants: These are associated with diseases or adverse health conditions. For example, a variant in the BRCA1 gene increases the risk of breast and ovarian cancer.
- Variants of Uncertain Significance (VUS): VUS are the ones where there is not enough evidence to determine their impact on health. These require further study and may eventually be reclassified as benign or pathogenic e.g. a novel missense mutation in a gene where its effect is unknown.
ACMG/AMP Variant Classification Guidelines
Genetic variants can be classified into five categories: pathogenic, likely pathogenic, uncertain significance (VUS), likely benign, and benign. The accurate classification of variants is essential for providing meaningful clinical information. However, differentiating between these categories can be difficult due to limited data, overlapping phenotypes, and incomplete penetrance. To address this challenge, clinical geneticists can rely on standardized guidelines, such as those provided by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). These guidelines offer criteria for evaluating the evidence supporting variant classification, including population data, computational predictions, functional studies, and segregation analysis. Regular updates to these guidelines ensure they reflect the latest scientific knowledge.
Recently there has been a great effort by ClinGen in refining the ACMG guidelines and streamlining the gene based variant interpretation. While the ClinGen consortium has already contributed significantly to genetic diagnosis of several disorders, the gene repertoire for the ClinGen guidelines are continuously emerging, and clinical and molecular geneticist are encouraged to get familiarize themselves with the ClinGen guidelines.
Challenges with Variants of Uncertain Significance (VUS)
VUS poses a significant challenge as they cannot be definitively classified as either pathogenic or benign. This uncertainty can complicate clinical decision-making and patient counseling.
To manage VUS, geneticists can adopt a multidisciplinary approach, integrating clinical data, family history, and additional functional studies when available.
- Involving genetic counselors, molecular pathologists, and other specialists can provide a more comprehensive evaluation.
- Periodic re-evaluation of VUS in light of new evidence, such as updated population databases and emerging research, can also help resolve some of these uncertainties over time.
- In our experience, familial segregation via targeted testing provides easy and accessible approach to clinically resolve VUS.
- RNA-seq can assist in determining the clinical significance of the VUS, particularly when the missense variants are predicted to impact splicing or critical genomic regions.
Incomplete and Biased Databases
Databases such as ClinVar, gnomAD, and HGMD are crucial for variant interpretation, but they can be incomplete or biased. These databases may lack representation of diverse populations, leading to misinterpretation of variant significance in underrepresented groups. Geneticists should contribute to and utilize population-specific databases to improve variant interpretation accuracy across different ethnicities. Collaborating with international consortia and initiatives aimed at increasing genetic diversity can enhance the reliability of these resources.
Interpretation of Non-Coding Variants
Most genetic research and variant interpretation focus on coding regions of the genome. However, non-coding regions, which make up the majority of the genome, also play critical roles in gene regulation and expression.
Interpreting variants in these regions remains challenging due to limited functional data.
In order to address the clinical significance of non-coding variants, it is recommended to check the functional importance of such variants.
Again, RNA-seq is a quick and informatic approach to get insight into such non-coding variants. Functional assays, such as reporter gene assays and CRISPR-based gene editing, can provide insights into the regulatory roles of non-coding regions. Collaboration with researchers specializing in non-coding DNA and the use of bioinformatics tools that predict regulatory elements can improve the interpretation of non-coding variants.
Ethical and psychological implications to variant interpretation
Interpreting genetic variants and communicating results have significant ethical and psychological implications.
Misinterpretation or uncertainty can cause anxiety, stress, and potential harm to patients and their families.
Genetic counseling is essential to help patients and families understand genetic findings. Geneticists should communicate results clearly and empathetically, providing support and resources to help patients cope with the information. Establishing a clear informed consent process and discussing potential outcomes before testing can prepare patients for possible results.
The interpretation of genetic variants is a complex task that requires careful consideration of various factors and challenges. As genetics evolves rapidly, continuous education and professional development are crucial for clinical molecular geneticists.
Interesting articles and publications on genetic variants and interpretation
