Glossary · Genetics
Genetic variant
In one sentence
A genetic variant is any difference in a person's DNA sequence compared with a reference sequence. Most have no effect on health; some are associated with disease or alter risk.
Also known as: genetic variants · sequence variant · sequence variants · pathogenic variant · pathogenic variants · variant of uncertain significance · variants of uncertain significance · VUS
What is a genetic variant?
Everyone carries millions of differences in their DNA compared with the human reference genome. Each of those differences is a genetic variant. The vast majority are common in the population and have no known effect on health; a small fraction can disrupt how a gene works and are associated with disease.
The 2015 ACMG/AMP guideline (Richards et al., Genetics in Medicine) recommends using “variant” with a modifier (pathogenic, likely benign and so on) rather than “mutation” or “polymorphism”, which had been used inconsistently.
Types of variant
By size and effect:
- Single nucleotide variants (SNVs): one base swapped for another. They can be synonymous, missense or nonsense.
- Small insertions and deletions (indels): when they shift the reading frame they are called frameshift variants.
- Splice-site variants: these affect how RNA is processed.
- Structural and copy number variants (CNVs): deletions, duplications or rearrangements of larger segments.
By origin, variants are either germline (inherited or present from the embryo, in every cell) or somatic (acquired in a tissue, as happens in tumours and is studied, for example, through liquid biopsy). They are described using HGVS nomenclature, which records the gene, position and change.
How it is classified
Once detected, usually by NGS, a variant is classified using the ACMG criteria into five tiers: pathogenic, likely pathogenic, uncertain significance (VUS), likely benign and benign. Evidence comes from population frequency, computational predictions, functional studies, family segregation and databases such as ClinVar.
Classification is not final. A VUS can be reclassified as evidence accumulates, and the relevance of any variant always depends on the condition and the clinical context.
Example
A hereditary cancer panel identifies a variant in a DNA repair gene. The report gives it in HGVS nomenclature, notes that it is very rare in population databases and classifies it as a VUS. The clinical geneticist explains to the referring oncologist that, for now, it does not change surveillance recommendations, and that the laboratory will review it if new evidence appears.
Genetic variants at Xenogene
Xenogene’s Clinvar platform is designed for genetic variant interpretation. According to its product page, it takes VCF files, annotates each variant with public data and predictors such as SIFT, PolyPhen-2 and CADD, classifies it according to ACMG/AMP criteria and produces clinical reports for genetic diagnosis and hereditary-family counselling. It should not be confused with the NCBI’s public ClinVar database, which is one of the sources it consults. The final interpretation rests with the professional who requested the analysis.
Frequently asked questions
What is a variant of uncertain significance (VUS)?
It is a variant for which there is not enough evidence to call it either pathogenic or benign. It should not be used on its own to guide clinical decisions, and its classification may change as new evidence emerges.
Is a variant the same as a mutation?
Current clinical practice prefers 'variant' together with a classification such as pathogenic or benign. The 2015 ACMG/AMP guideline recommends replacing 'mutation' and 'polymorphism' with 'variant', because those terms had been used inconsistently and could mislead.
If I carry a pathogenic variant, will I definitely develop the condition?
Not always. It depends on the gene, the inheritance pattern and penetrance, which is often incomplete. That is why such results come with genetic counselling from a qualified professional.
Related terms
- ACMG criteria
The ACMG criteria are the standards published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology for classifying genetic variants into five tiers, from pathogenic to benign.
- ClinVar
ClinVar is a free public database run by the NCBI at the US National Institutes of Health that collects interpretations submitted by laboratories and experts on how human genetic variants relate to disease.
- NGS (next-generation sequencing)
NGS (next-generation sequencing) is a family of technologies that read millions of DNA or RNA fragments in parallel in a single run, making it possible to study whole genomes, targeted genes or entire microbial communities at scale.
- Liquid biopsy
A liquid biopsy is the analysis of tumour-derived material, mainly circulating tumour DNA (ctDNA), in a body fluid such as blood. It allows genetic changes in a cancer to be studied without a tissue biopsy.
Educational content for healthcare professionals and the general public. It does not replace assessment by a healthcare professional: ordering and interpreting any test is the responsibility of the requesting clinician.
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