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Variant of uncertain significance
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Variant of uncertain significance
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. 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.
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. A 2016 study of genes commonly associated with hereditary breast and ovarian cancers; ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2 and TP53, found 15,311 DNA sequence variants in only 102 patients. Many of those 15,311 variants have no significant effect on the growth or health of the person in which they were found.
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. 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]
In 2001, an initial draft of the human genome was published by the International Human Genome Sequencing Consortium. 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. As of 2017[update], the cost of a quality whole genome sequence is $1,000 or less. If the ratio of approximately 20 DNA sequence variants per gene 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]
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. 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.
As of 2020[update], there continues to be limited involvement from federal agencies to regulate the clinical validity (accuracy) and utility (risks and benefits) of genetic testing. Variant interpretation and classification is notably subjective, as laboratories developed their own criteria prior to the ACMG-AMP guidelines. This subjectiveness is further problematic when there is evidence that variant significance changes over time. Due to the lack of consistency in official guidelines, the genomics community is left struggling to efficiently categorize genetic variants.
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.
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.
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Variant of uncertain significance
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. 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.
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. A 2016 study of genes commonly associated with hereditary breast and ovarian cancers; ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2 and TP53, found 15,311 DNA sequence variants in only 102 patients. Many of those 15,311 variants have no significant effect on the growth or health of the person in which they were found.
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. 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]
In 2001, an initial draft of the human genome was published by the International Human Genome Sequencing Consortium. 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. As of 2017[update], the cost of a quality whole genome sequence is $1,000 or less. If the ratio of approximately 20 DNA sequence variants per gene 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]
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. 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.
As of 2020[update], there continues to be limited involvement from federal agencies to regulate the clinical validity (accuracy) and utility (risks and benefits) of genetic testing. Variant interpretation and classification is notably subjective, as laboratories developed their own criteria prior to the ACMG-AMP guidelines. This subjectiveness is further problematic when there is evidence that variant significance changes over time. Due to the lack of consistency in official guidelines, the genomics community is left struggling to efficiently categorize genetic variants.
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.
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.
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