Commonly performed genetic testing (explain results only) - variants of uncertain significance (VOUS)

Definition

A variant of uncertain significance (VOUS/VUS) is a genetic sequence change identified on testing where current evidence is insufficient to classify it as either clearly pathogenic or clearly benign
VOUS results are common, particularly with broader gene panel and whole-exome/genome testing, which detects many more variants than can be confidently classified with current evidence - the more genes tested, the higher the chance of finding at least one VOUS

Variant classification follows a standardised framework (e.g. ACMG/AMP criteria) combining population frequency data, computational/in silico predictions, functional study evidence, segregation with disease in the family, and de novo occurrence - a VOUS reflects a gap in one or more of these evidence categories, not necessarily a truly ambiguous biological effect

A VOUS should NOT be used to guide clinical management (e.g. prophylactic surgery, altered surveillance, reproductive decisions) in the way a confirmed pathogenic variant would - this is a critical, frequently emphasised counselling point given the risk of overinterpretation
Variant classification can be reclassified over time as more evidence accumulates (population databases grow, functional studies are published, segregation data from more family members becomes available) - a VOUS today may later be reclassified as pathogenic or benign

Family segregation studies (testing additional affected/unaffected relatives to see whether the variant tracks with disease) and periodic re-review of variant classification (as laboratories/databases update) are the main tools to resolve a VOUS over time
Registering with the testing laboratory for update notifications ensures the patient/clinician is informed if the classification later changes

Hereditary cancer syndrome testing, cardiac genetic testing, any multi-gene panel or exome/genome sequencing

The majority of VOUS results are ultimately reclassified as benign/likely benign as more data accumulates, but this can take years - counselling should set realistic expectations about this uncertain interim period rather than implying an imminent resolution

5 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.