How do I understand my genetic test results?

Scientific advances have allowed us today to understand the most important part of our genetic code, providing valuable information for making decisions about our health.

When we undergo a genetic test, our doctor will receive a report that he or she will share with us, but do we understand all the information it includes? We are often confronted with technical language, full of acronyms such as SNP, CNV or VUS. Are all the changes detected in our DNA the same? Do they always imply a health risk?

In this article we will explain key concepts about genetic test results, allowing you to understand the different types of variants and what they mean.

Genetic Variant

A genetic variant is defined as an alteration in the DNA sequence, which can be beneficial, detrimental or neutral.

Genetic variation is inherent in human biology. The genome between two unrelated individuals differs by only about 0.1%. This diversity, for the most part, is what provides the individual differences in phenotype (observable traits) and generally does not lead to negative health consequences.

Types of Genetic Variants

Not all genetic variants are the same, which could have a functional impact on the genes and proteins they encode. The types most commonly identified in genomic analyses are:

Single nucleotide variants: as the name suggests, it is the change of one nucleotide for another at a given position in the DNA. Within this classification we have:

• SNPs (Single Nucleotide Polymorphisms): they are the most frequent type of variants and are found in more than 1% of the general population.
• SNVs (Single Nucleotide Variant): Regardless of their frequency in the population, they serve as a neutral descriptor that indicates a deviation from the reference sequence at a position in the genome.
• Indels (Small Insertions/Deletions): These consist of the insertion or deletion of a small number of DNA nucleotides. Any of these alterations (duplication, insertion, deletion or indels) can lead to a frameshift, which usually generates a stop codon and premature termination of the associated protein. This usually reduces or completely eliminates its activity, causing the associated pathology.
• CNVs (Copy Number Variations): They involve the gain or loss of large DNA fragments and can affect part of a gene or several complete genes, generating more or fewer copies than normal. They are often a major cause of various genetic syndromes (such as the 22q11.2 deletion associated with DiGeorge syndrome).

Classification of variants

Interpreting the functional significance and clinical relevance of a specific variant is part of the diagnostic challenge. To standardize this interpretation, the scientific community, through rigorous guidelines such as those of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), has established a classification system in five categories:

• Pathogenic
• Probably Pathogenic
• Uncertain Significance (VUS)
• Probably Benign
• Benign

We all have variants in our DNA, but a correct interpretation and classification is key to understand if there is clinical relevance.

When a Variant of Uncertain Significance (VUS) is obtained in a genetic report, many doubts can arise as to what exactly it means.

A VUS is a genetic variant for which, with the scientific knowledge available at this time, there is insufficient evidence to determine with certainty whether it is benign or pathogenic (disease-causing). In the event that a variant does not meet some or more of the classification criteria to be considered benign or pathogenic, that variant will be considered a VUS. The finding of a VUS requires a cautious interpretation integrated into the complete clinical context of the patient: detailed phenotype, personal and family history, and the results of other complementary examinations.In patients with a particular pathology or a compatible family history, a VUS becomes a ‘candidate variant’ that warrants further investigation. Family segregation studies look at the presence of the same VUS in other family members. If the VUS ‘travels’ consistently with the disease (present in affected, absent in healthy), the evidence favors its pathogenicity significantly. Conversely, if VUS is found in healthy relatives and is absent in the affected, the evidence points toward a benign classification. These studies are crucial in attempting to reclassify VUS and clarify its true clinical significance for the family.

A VUS can and should be reevaluated periodically, and may be reclassified in the future as (probably) benign or (probably) pathogenic. Therefore, long-term follow-up and smooth communication between the clinician, the patient and the laboratory is essential.

The Classification Process

Classifying a genetic variant requires expert analysis and thoughtful integration of multiple lines of evidence, following international standardized guidelines (mainly ACMG/AMP). Geneticists and bioinformaticians systematically evaluate criteria such as:

• Databases: In databases we find the classification of clinical variants by expert groups or by other users with knowledge in genetics. Databases can be public access, paid or even proprietary (e.g. ClinVar, HGMD, etc.).

• Population Data: Allele frequency in large population reference databases. A high frequency in the general population usually implies that the variant is benign.

• Computational Data (In Silico): Use of multiple predictive algorithms that estimate the possible deleterious impact of the variant on the sequence or structure of the protein, or on regulatory elements.

• Functional Data: Results of experimental studies (in vitro or in vivo) that directly assess the effect of the variant on gene or protein function (e.g. enzymatic assays, expression studies, cellular localization).

• Segregation data: Analysis of the co-occurrence of the variant with the disease in members of the same family. If the variant segregates with the expected phenotype according to the inheritance pattern.

• De Novo Data: If the variant appears for the first time in the patient, without being present in his progenitors, it is an additional criterion of pathogenicity. For this reason, trio studies (proband and progenitors) are important, this is especially relevant in diseases of early onset and high penetrance.

• Variant Type and Location: Is it a loss-of-function variant (nonsense, frameshift, canonical splicing site) in a gene where this mechanism is known to be pathogenic? Does it affect a critical functional domain of the protein? These are relevant questions for assessing pathogenicity.

• Other Data: Published scientific literature, homology with other species, etc. are also evaluated.

Knowledge of these key concepts encourages more informed patient participation in their own care and facilitates a more productive dialogue with healthcare professionals. However, we reiterate the indispensable need for expert, contextualized genetic counseling. The final interpretation of any genetic findings and subsequent clinical decisions should always be made under the guidance of qualified professionals, integrating genomic information with each individual’s unique clinical and family history.