Variant of uncertain significance

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A VUS is a common result in genetic testing VUS report.jpg
A VUS is a common result in genetic testing

A variant of uncertain (or unknown) significance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known. [1] Two related terms are "gene of uncertain significance" (GUS), which refers to a gene that has been identified through genome sequencing but whose connection to a human disease has not been established, and "insignificant mutation", referring to a gene variant that has no impact on the health or function of an organism. The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely (i.e. without inherently connoting pathogenicity). When the variant has no impact on health, it is called a "benign variant". When it is associated with a disease, it is called a "pathogenic variant". A "pharmacogenomic variant" has an effect only when an individual takes a particular drug and therefore is neither benign nor pathogenic. [1]

Contents

A VUS is most commonly encountered by people when they get the results of a lab test looking for a mutation in a particular gene. For example, many people know that mutations in the BRCA1 gene are involved in the development of breast cancer because of the publicity surrounding Angelina Jolie's preventative treatment. [2] Few people are aware of the immense number of other genetic variants in and around BRCA1 and other genes that may predispose to hereditary breast and ovarian cancer. A recent study of the genes ATM , BRCA1, BRCA2 , CDH1, CHEK2 , PALB2 and TP53 found 15,311 DNA sequence variants in only 102 patients. [3] Many of those 15,311 variants have no significant phenotypic effect. That is, a difference can be seen in the DNA sequence, but the differences have no effect on the growth or health of the person. [3]

Identifying variants that are significant or likely to be significant is a difficult task that may require expert human and in silico analysis, laboratory experiments and even information theory. [3] In spite of those efforts, many people may be worried about their particular VUS, even though it has not been determined to be significant or likely to be significant. Most discovered VUSs will not be investigated in a peer-reviewed research paper, as this effort is usually reserved for likely pathogenic variants.[ citation needed ]

History

In 2001, an initial draft of the human genome was published by the International Human Genome Sequencing Consortium. [4] With the development of next-generation sequencing, the cost of sequencing has plummeted and the number of human genomes and exomes sequenced each year is increasing dramatically. [5] As of 2017, the cost of a quality whole genome sequence is $1,000 or less. [6] If the ratio of approximately 20 DNA sequence variants per gene [3] holds over the entire genome (with approximately 20,000 genes) that means that every person who elects to have their genome sequenced will be provided with almost half a million Variants of Unknown Significance. To assist people to understand the meaning of all these variants, classification is a first step.[ citation needed ]

Classification

Since the Human Genome Project first sequenced the human genome in 2001 at a cost of US$100 million, costs have fallen precipitously, outpacing even Moore's law, and were [?]US$1,000 in 2015. More widely available genome sequencing has led to more available data on variants of uncertain significance. Cost per Genome.png
Since the Human Genome Project first sequenced the human genome in 2001 at a cost of US$100 million, costs have fallen precipitously, outpacing even Moore's law, and were ≈US$1,000 in 2015. More widely available genome sequencing has led to more available data on variants of uncertain significance.

In 2015, the American College of Medical Genetics and Genomics (ACMG), the Association for Molecular Pathology (AMP), and the College of American Pathologists (CAP) published a third revision of their guidelines on variant interpretation in Mendelian disorders. [1] The publication recommended the following categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. This guideline is one of many resources published by the ACMG in hopes of improving standardization of variant interpretation and reporting. [1] [7] [8] [9] [10]

As of 2020, there continues to be limited involvement from federal agencies to regulate the clinical validity (accuracy) and utility (risks and benefits) of genetic testing. [11] [12] [13] Variant interpretation and classification is notably subjective, as laboratories developed their own criteria prior to the ACMG-AMP guidelines. [8] [9] [14] This subjectiveness is further problematic when there is evidence that variant significance changes over time. [13] Due to the lack of consistency in official guidelines, the genomics community is left struggling to efficiently categorize genetic variants. [9] [15] [16]

Pathogenic

This category is reserved for variants that are well-documented to cause disease. Pathogenicity should be reported with respect to a specific condition and inheritance pattern (e.g., autosomal recessive or dominant). A pathogenic variant meets stringent criteria such as evidence from well-established functional studies or being identified in multiple unrelated individuals with the disease. [1]

Likely pathogenic

Variants in this category show strong evidence of being disease-causing but lack definitive proof. The term “likely pathogenic” indicates that the data supports a high likelihood (greater than 90%) that the variant is pathogenic. [1]

Uncertain significance

This category is for variants where there is unknown or conflicting clinical significance. Additional evidence is needed in order to determine whether or not the variant is causative for a particular disease. [1] As additional data and research emerges over time, variants of unknown significance may get moved to other categories, frequently towards the benign or likely benign categories. [17]

Likely benign

This category is used for variants that are unlikely to be causative of disease, typically supported by population frequency data or functional studies suggesting no deleterious impact. A “likely benign” classification implies more than 90% certainty that the variant is not causative for a disease. [1]

Benign

This category is for variants that are not disease-causing. These variants are usually observed at high frequencies in population databases and have strong evidence against a pathogenic effect, including predictive computational models and experimental data showing no effect on the encoded protein. [1]

Limitations of the classifications

Less than 5% of the human genome encodes proteins, and the rest is associated with non-coding RNA molecules, regulatory DNA sequences, LINEs, SINEs, introns, and sequences for which as yet no function has been determined. [4] Thus, only a small fraction of the almost half-million VUS's that are expected to be identified by whole genome sequencing can be categorized into the 5 categories above, leaving the patient nearly as uninformed about their variants as they would have been without this information.[ citation needed ]

Most of the base sequences regulating gene expression are found outside of protein-coding sequences, either within introns or outside of genes in intergenic regions. Changes in those regulatory regions can lead to dysfunction of a gene(s) and produce phenotypic effects that can be relevant to health and function. [18]

An example of a variant in an intergenic enhancer is one that is associated with blond hair color in northern Europeans. The variant in an enhancer of the KITLG gene causes only a 20% change in gene expression, yet causes hair lightening. [18] [19]

An example of an intronic VUS controlling gene expression is the SNP found in an intron of the FTO gene. The FTO gene encodes the fat mass and obesity-associated protein, and the SNP (or VUS) found in its intron was shown by genome-wide association studies to be associated with an increased risk for obesity and diabetes. The initial assumption was that this mutation was misregulating FTO to cause the disease risk. However, it was later shown that the intronic variant was in fact regulating the distant IRX3 gene and not the FTO gene. [20] That is just one example of how difficult it can be to determine the significance of a VUS even when many research labs are focused on it, and it illustrates that clinicians cannot reliably interpret genetic results that have not been fully clarified by prior research.[ citation needed ]

Applications

The number of VUS reports makes it impossible to mention all such reports. To give a flavor for some applications in one field, it is perhaps of most interest to focus on breast cancer. Remember, this is only a fraction of the information available world-wide about VUS reports related to breast cancer, and as always, your results may vary.[ citation needed ]

In a 2009 US study of over 200 women who received BRCA VUS reports and were surveyed for one year thereafter, distress over the result persisted for the year. [21]

A 2012 survey of patient outcomes in the Netherlands found that, after genetic counseling for BRCA VUS, patients perceived themselves to have different cancer risks than what had been explained to them by genetic counselors, and that this misperception influenced decisions about radical medical procedures. [22]

In a 2015 study in the UK, where BRCA VUSs occur in 10-20% of tests, 39% of breast cancer specialists taking part in the study did not know how to explain a VUS report to a patient with no family history, and 71% were unsure about the clinical implications of the test reports. [23]

Related Research Articles

<span class="mw-page-title-main">Penetrance</span> Proportion of individuals that express the trait associated with an allele

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. For example: If a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will go on to develop the disease, showing its phenotype, whereas 5% will not. 

<span class="mw-page-title-main">Genetic testing</span> Medical test

Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or through biochemical analysis to measure specific protein output. In a medical setting, genetic testing can be used to diagnose or rule out suspected genetic disorders, predict risks for specific conditions, or gain information that can be used to customize medical treatments based on an individual's genetic makeup. Genetic testing can also be used to determine biological relatives, such as a child's biological parentage through DNA paternity testing, or be used to broadly predict an individual's ancestry. Genetic testing of plants and animals can be used for similar reasons as in humans, to gain information used for selective breeding, or for efforts to boost genetic diversity in endangered populations.

<span class="mw-page-title-main">Single-nucleotide polymorphism</span> Single nucleotide in genomic DNA at which different sequence alternatives exist

In genetics and bioinformatics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently large fraction of the population, many publications do not apply such a frequency threshold.

<span class="mw-page-title-main">Medical genetics</span> Medicine focused on hereditary disorders

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.

<span class="mw-page-title-main">Incidental medical findings</span> Undiagnosed medical or psychiatric conditions discovered unintentionally during evaluation

Incidental medical findings are previously undiagnosed medical or psychiatric conditions that are discovered unintentionally and during evaluation for a medical or psychiatric condition. Such findings may occur in a variety of settings, including routine medical care, during biomedical research, during post-mortem autopsy, or during genetic testing.

<span class="mw-page-title-main">Mary-Claire King</span> American geneticist

Mary-Claire King is an American geneticist. She was the first to show that breast cancer can be inherited due to mutations in the gene she called BRCA1. She studies human genetics and is particularly interested in genetic heterogeneity and complex traits. She studies the interaction of genetics and environmental influences and their effects on human conditions such as breast and ovarian cancer, inherited deafness, schizophrenia, HIV, systemic lupus erythematosus and rheumatoid arthritis. She has been the American Cancer Society Professor of the Department of Genome Sciences and of Medical Genetics in the Department of Medicine at the University of Washington since 1995.

<span class="mw-page-title-main">Myriad Genetics</span> American biotechnology company

Myriad Genetics, Inc. is an American genetic testing and precision medicine company based in Salt Lake City, Utah, United States. Myriad employs a number of proprietary technologies that permit doctors and patients to understand the genetic basis of human disease and the role that genes play in the onset, progression and treatment of disease. This information is used to guide the development of new products that assess an individual's risk for developing disease later in life, identify a patient's likelihood of responding to a particular drug therapy, assess a patient's risk of disease progression and disease recurrence, and measure disease activity.

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<span class="mw-page-title-main">Hereditary breast–ovarian cancer syndrome</span> Medical condition

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Personal genomics or consumer genetics is the branch of genomics concerned with the sequencing, analysis and interpretation of the genome of an individual. The genotyping stage employs different techniques, including single-nucleotide polymorphism (SNP) analysis chips, or partial or full genome sequencing. Once the genotypes are known, the individual's variations can be compared with the published literature to determine likelihood of trait expression, ancestry inference and disease risk.

<span class="mw-page-title-main">Whole genome sequencing</span> Determining nearly the entirety of the DNA sequence of an organisms genome at a single time

Whole genome sequencing (WGS) is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's chromosomal DNA as well as DNA contained in the mitochondria and, for plants, in the chloroplast.

<span class="mw-page-title-main">Exome sequencing</span> Sequencing of all the exons of a genome

Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome. It consists of two steps: the first step is to select only the subset of DNA that encodes proteins. These regions are known as exons—humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs. The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology.

<i>BRCA</i> mutation Medical condition

A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast–ovarian cancer syndrome in affected persons. Only 5–10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations, but the impact on women with the gene mutation is more profound. Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal. The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor.

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<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

<span class="mw-page-title-main">Molecular diagnostics</span> Collection of techniques used to analyze biological markers in the genome and proteome

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Personalized onco-genomics (POG) is the field of oncology and genomics that is focused on using whole genome analysis to make personalized clinical treatment decisions. The program was devised at British Columbia's BC Cancer Agency and is currently being led by Marco Marra and Janessa Laskin. Genome instability has been identified as one of the underlying hallmarks of cancer. The genetic diversity of cancer cells promotes multiple other cancer hallmark functions that help them survive in their microenvironment and eventually metastasise. The pronounced genomic heterogeneity of tumours has led researchers to develop an approach that assesses each individual's cancer to identify targeted therapies that can halt cancer growth. Identification of these "drivers" and corresponding medications used to possibly halt these pathways are important in cancer treatment.

<span class="mw-page-title-main">Cancer pharmacogenomics</span>

Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.

Personalized genomics is the human genetics-derived study of analyzing and interpreting individualized genetic information by genome sequencing to identify genetic variations compared to the library of known sequences. International genetics communities have spared no effort from the past and have gradually cooperated to prosecute research projects to determine DNA sequences of the human genome using DNA sequencing techniques. The methods that are the most commonly used are whole exome sequencing and whole genome sequencing. Both approaches are used to identify genetic variations. Genome sequencing became more cost-effective over time, and made it applicable in the medical field, allowing scientists to understand which genes are attributed to specific diseases.

References

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  21. ↑ O'Neill SC, Rini C, Goldsmith RE, Valdimarsdottir H, Cohen LH, Schwartz MD (October 2009). "Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes". Psycho-Oncology. 18 (10): 1088–96. doi:10.1002/pon.1467. PMC   3503506 . PMID   19214961.
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