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Counselling about variants of uncertain significance and incidental findings

How to explain a VUS and what to do (and not do) with it, how often VUS are reclassified, the difference between incidental and secondary findings, the ACMG SF v3.3 list, and unexpected findings such as consanguinity on microarray or maternal cancer on NIPT.

Tier 2Topic overview

Written with AI assistance and fact-checked against the sources below. For exam study, not clinical decisions. How notes are made

3 questions 8 flashcards

At a glance

A variant of uncertain significance (VUS) is not a diagnosis and not a mild pathogenic variant. It is a statement that the evidence is insufficient either way. Classification rules are in variant classification.
Don't act on it: no predictive testing of relatives, no risk-reducing surgery, no change to surveillance beyond what history already justifies.
Most VUS that are reclassified go down, to likely benign or benign.

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Sources

ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the ACMG. Genet Med 2025;27(8):101454American College of Medical Genetics and Genomics, 2025
Requirements for medical testing for human genetic variation, fourth edition (NPAAC), standards 1.03 to 1.08AU/NZAustralian Commission on Safety and Quality in Health Care, 2025, amended March 2026
Mersch J et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA 2018;320:1266-1274JAMA, 2018
Richards S et al. Standards and guidelines for the interpretation of sequence variants (ACMG/AMP). Genet Med 2015;17:405-24Genetics in Medicine, 2015
Shariant variant sharing platformAU/NZAustralian Genomics

Last updated: 14 November 2026

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