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# Interpreting genetic variants: classes, evidence and databases

Finding a DNA change is the easy part; deciding whether it causes disease uses population data, prediction, family studies and shared databases.

Updated Nov 13, 2026

## Key facts

- Variants are classed in five tiers: pathogenic, likely pathogenic, uncertain significance (VUS), likely benign and benign (ACMG/AMP standard).
- Evidence comes from population frequency, the predicted effect on the protein, functional studies, segregation with disease in the family, de novo occurrence and previous reports.
- A variant that is more common in healthy people than the disease allows is very unlikely to cause it; population databases such as gnomAD give these frequencies.
- A VUS must not guide medical decisions; it is followed up and may be reclassified, most often as benign.
- Shared databases: ClinVar (interpretations submitted by laboratories), gnomAD (frequencies), OMIM (genes and disorders), DECIPHER (copy-number changes).

## In detail

- Exome or genome analysis filters thousands of variants by quality, rarity, predicted effect, the inheritance pattern that fits the family (de novo, biallelic, X-linked) and how well the gene matches the patient's features.
- Most reference data come from people of European ancestry, so people from under-represented populations, including Latin Americans, receive more uncertain results and sometimes wrong classifications.
- Interpretation changes as knowledge grows; laboratories reanalyse old results, and patients should know that a report can be updated.
- Pathogenic means the variant can cause the disease; whether a given person develops it still depends on penetrance.

**Also called**
Variant of uncertain significance (VUS), ACMG classification, ClinVar and gnomAD

## Clinical notes

- A BRCA2 VUS does not justify risk-reducing surgery; management follows the personal and family history.
- Testing relatives to see whether a variant tracks with the disease can help reclassify it.

## Test yourself

Think of the answer, then tap the question to see it.

## What are the five classes of a genetic variant?

Pathogenic, likely pathogenic, uncertain significance, likely benign and benign.

## How do population databases help interpret a variant?

A variant too frequent in healthy people for the prevalence of the disease is unlikely to be its cause.

## Why do people of under-represented ancestry get more uncertain results?

Reference databases contain fewer people like them, so rare-but-harmless variants in their populations look unusual and uncertain.

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## Connections

## Related conditions 2

- [Hereditary breast and ovarian cancer syndrome (BRCA1/BRCA2)](https://durgical.com/en/conditions/hereditary-breast-and-ovarian-cancer-syndrome/)
- [Lynch syndrome (hereditary non-polyposis colorectal cancer)](https://durgical.com/en/conditions/lynch-syndrome/)

## Related 5

- [Genetic tests: what each one finds](https://durgical.com/en/biochemistry/topics/genetic-tests-what-each-one-finds/)
- [DNA sequencing](https://durgical.com/en/biochemistry/topics/dna-sequencing/)
- [Population genetics: Hardy–Weinberg and carrier frequency](https://durgical.com/en/biochemistry/topics/population-genetics-hardy-weinberg-and-carrier-frequency/)
- [Types of mutations](https://durgical.com/en/biochemistry/topics/types-of-mutations/)
- [DNA polymorphisms, linkage and DNA fingerprinting](https://durgical.com/en/biochemistry/topics/dna-polymorphisms-linkage-and-dna-fingerprinting/)

Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology](https://pubmed.ncbi.nlm.nih.gov/25741868/) (Genetics in Medicine (Richards S et al.), PubMed 25741868, 2015); [What do the results of genetic tests mean?: MedlinePlus Genetics](https://medlineplus.gov/genetics/understanding/testing/interpretingresults/) (MedlinePlus, US National Library of Medicine, 2026); [gnomAD](https://gnomad.broadinstitute.org/) (Genome Aggregation Database, Broad Institute, 2026); [Bioinformatics](https://www.genome.gov/genetics-glossary/Bioinformatics) (National Human Genome Research Institute (NHGRI), 2026).

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