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Variants of Uncertain Significance: What You Need To Know

Variants of Uncertain Significance:

What You Need To Know

Variation in the human genome is extensive, with new genetic changes being discovered daily. In the evolving world of genetic testing, variants of uncertain significance (VUS) are expected. A variant of uncertain significance is a change in the normal sequence of a gene for which the clinical significance and/or association with disease is unclear. Even after detecting tens of thousands of unique variants, Myriad identifies approximately 75 new variants every day, including 5-10 new BRCA1/2 variants (Myriad Internal Data).

The Myriad Variant Classification Program, myVision™, is the industry leader in variant classification and reclassification. The myVision™ program encompasses a lifetime commitment to accurate and clinically significant results for all patients and families. To learn more about the myVision™ Variant Classification Program, click here.

In accordance with the American College of Medical Genetics guidelines1, Myriad utilizes a five-tier variant classification system composed of the following categories: ‘deleterious’ (pathogenic), ‘suspected deleterious’ (likely pathogenic), ‘variant of uncertain clinical significance’ (VUS), ‘genetic variant, favor polymorphism’ (favor normal human variation, likely not pathogenic) and ‘polymorphism’ (normal human variation only, not pathogenic)1.  If a variant of uncertain significance is reclassified, the ordering healthcare provider will receive an amended report. Currently, Myriad sends out approximately 250 amended reports per week (Myriad Internal Data).

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Variant classifications illustrated in increasing risk, similar to climbing the rungs of a ladder.

The myRisk Hereditary Cancer™ report provides recommendations for managing patients based on genetic and familial risk. Every report includes: genetic test results, guideline-based medical management considerations for negative and positive patients (either of which may contain variants of uncertain significance) and information for family members. To view sample reports, click here.

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What do variants of uncertain significance (VUS) mean for your practice?

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Negative Green Bar Results:

No clinically significant mutations detected (normal variation)

  • Definition: negative

Variant, Favor Polymorphism

  • Definition: very likely negative
  • Interpretation: cause of cancer in family has not been determined; patient may have increased risk based on family history
  • Management: based on personal and family history

Genetic Variant of Uncertain Significance (VUS)

  • Definition: inconclusive
  • Interpretation: a genetic change that is different from normal control has been identified. The vast majority of VUS results are ultimately reclassified and given definitive classifications. Evidence for each VUS is evaluated consistently. Whether reclassified to positive or negative, the healthcare provider will receive an amended report with the updated classification
  • Management: based on personal and family history; clinical single site testing for a VUS in relatives is not recommended

Note: This does not apply when a known family mutation has already been identified. In this case, the patient would be considered a true negative and not at an elevated, familial risk for cancer in most cases.

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Positive Red Bar Results:

Variant, Suspected Deleterious

  • Definition: very likely positive
  • Interpretation: patient has a genetic change that is suspected to cause gene-related risks and/or syndrome
  • Management: according to guidelines for gene and/or syndrome; suggest single site testing for family members

Positive for Deleterious Mutation

  • Definition: positive
  • Interpretation: patient is confirmed to have the gene-related risks and/or syndrome; cancer risks defined by gene and/or syndrome*
  • Management: according to guidelines for gene and/or syndrome; suggest single site testing for family members

Note: Patients may carry variants of uncertain significance in addition to their deleterious or suspected deleterious result.

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The myVision™ Variant Classification Program

The myVision™ Variant Classification Program (VCP) has 20 years of experience with >$100,000,000 invested, data from >1.5 million patients and family members and the expertise of over 30 scientists2. This team utilizes various methodologies for variant classification and reclassification. For example, Myriad has developed a unique quantitative methodology (PhenoTM) that carries a >99.9% positive and negative predictive value3. In addition, Myriad’s LitVIEWTM algorithm for evaluating the literature and inSITETM RNA studies are unique to Myriad and aid in variant reclassification. Through myVision™, Myriad has dramatically reduced the VUS rates for Myriad’s genetic tests, thereby providing the most accurate, clinically actionable results for patients.

 

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For additional information regarding variant classification techniques, including a case study on reclassification, click here.

 
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Bottom Line:

The myVision™ Variant Classification Program encompasses a lifetime commitment to accurate and clinically significant results for all patients and families. To learn more about the industry leading myVision™ Variant Classification Program, click here.

 

REFERENCES

1. Richards CS, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisionsn 2007. Genet Med 2008: 10: 294-300. http://www.ncbi.nlm.nih.gov/pubmed/18414213

2. Eggington JM, et al. A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clin Genet 2014 Sep; 86(3): 229-37. http://www.ncbi.nlm.nih.gov/pubmed/24304220

3. Pruss D, et al. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 2014 Aug; 147(1): 119-32. http://www.ncbi.nlm.nih.gov/pubmed/25085752

If you have questions regarding this topic, please contact your local Regional Medical Specialist (RMS)

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