99.5% of all DNA is shared across all humans; it is the 0.5% that makes all the difference. Genetic variations, or variants, are the differences that make each person’s genome unique (see What is a genome?). DNA sequencing identifies an individual’s variants by comparing the DNA sequence of an individual to the DNA sequence of a reference genome maintained by the Genome Reference Consortium (GRC).
There are different ways that one person’s DNA sequence can differ from the reference DNA sequence, some of which are:
- Single nucleotide polymorphisms (“SNPs”, pronounced “snips”) are DNA sequence variations that occur when a single nucleotide differs from the reference DNA sequence.
- Insertions are when additional nucleotides inserted in a DNA sequence, relative to the reference sequence.
- Deletions are when there are missing nucleotides, relative to the reference sequence.
- Substitutions are when multiple nucleotides are altered from the reference sequence.
- Structural variants are changes where large sections of a chromosome or even whole chromosomes are duplicated, deleted or rearranged in some manner.
The average person’s genome has millions of variants. Some variants occur in genes but most occur in DNA sequences outside of genes. A small number of variants have been linked with diseases, but most variants have unknown effects. Some variants contribute to the differences between humans, such as different eye colors and blood types. As more DNA sequence information becomes available to the research community, the effects of some variants may be better understood.
The American College of Medical Genetics and Genomics (ACMG) has developed guidelines for the classification of DNA sequence variants:
- Pathogenic - a sequence variant that is previously reported and is a recognized cause of the disorder.
- Likely Pathogenic – a sequence variant that is previously unreported and is of the type which is expected to cause the disorder.
- VUS (Variant of Unknown Significance) – a sequence variant that is previously unreported and is of the type which may or may not be causative of the disorder.
- Likely Benign – a sequence variant that is previously unreported and is probably not causative of disease.
- Benign – a sequence variant is previously reported and is a recognized neutral variant.
- A sequence variant that is previously not known or expected to be causative of disease, but is found to exist in people with a particular disease or disorder.
Understanding the effects of variants is a very complicated process. While there are many publicly available sources of information about variants and their classification based on ACMG guidelines that link variants to diseases, knowledge about variants is constantly evolving and inconsistencies and inaccuracies can be found in these sources. Any health-related matters should be directed to your doctor or another qualified medical professional.