Course : MOC Part IV: Variant of Uncertain Significance (VUS) Result Updating

Next generation sequencing technology has transformed clinical genetic testing and allowed for an ever-increasing number of available testing options. With the expansion of testing, clinical laboratories are increasingly detecting variants in genes associated with genetic disorders. Although detection of variants in an individual’s nucleotide sequence has become simpler with the advent of new technology, determining the effect of the variants on a person’s health often is difficult.1 consequently, a number of identified variants are classified as variants of uncertain significance.2

As evidence on variants advances, classifications may require modification. The American College of Medical Genetics recognizes that laboratories should make an effort to contact providers concerning new clinical interpretations of variants of uncertain significance.3 At the same time, the College contends that, as the number of variants grows, the ability of laboratories to update reports may be unsustainable. Therefore at the time of the patient’s re-evaluation, health-care providers should inquire about variants of uncertain significance to determine if knowledge of the variant has changed.

In addition to re-contacting the genetic testing laboratory that performed testing, clinical geneticists can gather additional information to explore as completely as possible the clinical significance of a variant. Clinicians can contact the patient to update his/her clinical features to determine if his/her phenotype has changed since the variant was reported. Phenotypic information can impact the interpretation of genomic variants. Clinicians also can search available literature and variant databases such as Pubmed, ClinVar, Human Gene Mutation Database (HGMD), and population databases to determine if the variant has been reported by other clinical laboratories or researchers.1  

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