Understanding Genomics

In brief

When a genetic test identifies a DNA variant, laboratories assess the available scientific evidence to determine whether that variant is associated with disease. Most clinical laboratories use a five-tier classification system ranging from benign to pathogenic. Sometimes there is not yet enough evidence to reach a clear conclusion, resulting in a Variant of Uncertain Significance (VUS). As scientific knowledge continues to grow, some variant classifications may be updated over time.

How are genetic variants classified?

Clinical laboratories evaluate multiple sources of evidence when interpreting genetic variants. These may include population studies, laboratory research, computer-based prediction tools, family studies, and information reported in scientific and clinical databases.

Most laboratories follow internationally recognised guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). In the UK, these principles are further refined by the Association for Clinical Genomic Science (ACGS) for clinical practice. The relevant ACMG/AMP and ACGS guidance documents are provided under "Further reading" below.

Variants are usually classified into five categories:

• Pathogenic – strong evidence that the variant causes disease.

• Likely pathogenic – the evidence strongly suggests the variant causes disease, although a small degree of uncertainty remains.

• Variant of Uncertain Significance (VUS) – current evidence is insufficient to determine whether the variant is disease-causing or harmless.

• Likely benign – the evidence strongly suggests the variant does not cause disease.

• Benign – strong evidence that the variant does not cause disease.

What does "pathogenic" mean?

A pathogenic variant is one for which there is strong scientific evidence that it causes a particular genetic condition.

Importantly, a pathogenic classification does not necessarily mean that a person currently has a disease. Likewise, it does not necessarily determine whether symptoms will develop, when they will appear, or how severe they may become. The clinical impact of a pathogenic variant may depend on several factors, including the condition involved, the pattern of inheritance, age, environmental influences, and—in some cases—other genetic factors.

What is a Variant of Uncertain Significance (VUS)?

A VUS means that there is currently not enough evidence to determine whether the variant is associated with disease.

A VUS is not a diagnosis, nor should it generally be used on its own to guide medical management. Instead, it indicates that additional research or clinical evidence is needed before the variant can be classified more confidently.

As new information becomes available, such as:

• studies involving larger populations,

• laboratory research,

• reports from other individuals with the same variant, or

• additional family testing,

the classification may become clearer over time.

Can genetic test results change over time?

For inherited (germline) genetic testing, the DNA sequence itself does not change, but our understanding of a genetic variant can.

As scientific knowledge expands, some variants are reclassified to reflect new evidence. For example, a VUS may later be reclassified as likely pathogenic, pathogenic, likely benign, or benign. Reclassification between pathogenic or likely pathogenic and benign or likely benign categories is also possible, but such changes remain rare (see the publication by Kobayashi et al. listed under "Further reading").

For this reason, a genetic test report should be interpreted as reflecting the best available evidence at the time it was issued.

Why can classifications change?

Advances in genomic research continue to improve our understanding of how genetic variants influence health and disease. New evidence may include:

• larger and more diverse population databases;

• functional laboratory studies;

• improved understanding of disease mechanisms;

• information from families with similar genetic findings; and

• updated international interpretation guidelines.

These developments help laboratories make more accurate variant interpretations over time.

Key takeaway

A genetic variant classification reflects the current scientific evidence, not absolute certainty. A pathogenic variant has strong evidence supporting its role in disease, while a Variant of Uncertain Significance indicates that more evidence is needed before a conclusion can be reached. As genomic research continues to advance, some variant classifications may change, allowing genetic variants to be interpreted with increasing confidence.

Further reading

If you would like to explore this topic in more detail, you may find the following evidence-informed resources helpful:

• Richards S, et al; ACMG Laboratory Quality Assurance Committee. 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. Genet Med. 2015;17(5):405-24. PMID: 25741868.

• Manolio TA, et al. Opportunities, resources, and techniques for implementing genomics in clinical care. Lancet. 2019;394(10197):511-520. PMID: 31395439.

• Durkie M, et al. ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024. ACGS Guidelines. [Accessed on 11/07/2026]

• Kobayashi Y, et al. Clinical Variant Reclassification in Hereditary Disease Genetic Testing. JAMA Netw Open. 2024;7(11):e2444526. PMID: 39504018.

Continue Exploring (Member Resource)

Members can explore this topic in greater depth through the accompanying feature article available within the Discern Genomics Member Portal, together with related learning resources. These materials expand on the scientific evidence, practical implications, and opportunities for further reflection.