Reading a VUS

Written By Kanna Nandakumar
Reading a VUS: What the Result Obligates You to Do — and What It Does Not | Zetobit
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Reading the Report
READING THE REPORT Reading a VUS What the result obligates you to do — and what it does not Kanna Nandakumar, PhD Zetobit, LLC · Bioinformatics Consulting

Reading the Report

Reading a VUS: What the Result Obligates You to Do — and What It Does Not

First in a series written for the people who receive genomic output rather than produce it: what a document establishes, what it leaves open, and what to ask about the difference.

Kanna Nandakumar, PhD  ·  Zetobit, LLC

A germline panel comes back and most of it is unremarkable. One line is not. It names a gene, a nucleotide change, a protein consequence, and then a classification: variant of uncertain significance.

The report is precise about what the laboratory found and nearly silent about what you should do next, because that part was never the laboratory's to decide. The result is now sitting in a chart, in front of a clinician who has to make a decision this week and a patient who has already read the phrase and drawn a conclusion from it. This piece is about what that line obligates you to do — and, more consequentially, what it does not.

The classification is a statement about the evidence, not about the variant

It is natural to read the five-tier scale as a spectrum: pathogenic at one end, benign at the other, uncertain somewhere in the middle. That reading is wrong in a way that matters clinically. The variant either disrupts the protein and confers risk, or it does not; nothing about it is intermediate. What is uncertain is the evidence available to the laboratory on the day it wrote the report.

A VUS is therefore not a weak positive. It is the absence of a result. This is why the ACMG/AMP framework states plainly that a variant of uncertain significance should not be used in clinical decision making1 — and why the corollary is equally binding: it cannot be used to reassure, either. A VUS does not raise the patient's risk and it does not lower it. It leaves risk exactly where the personal and family history put it.

MOLECULAR GENETICS REPORT ILLUSTRATIVE REPORT DATE 14 MAR 2024 TEST PERFORMED Hereditary cancer panel, 84 genes RESULT ATM c.5432A>G p.(Asn1811Ser) VARIANT OF UNCERTAIN SIGNIFICANCE This variant has not been reported in the peer- reviewed literature in individuals with this condition. Available population and computational data are insufficient to determine its role in disease. Clinical correlation is recommended. Classification reflects the evidence available as of the report date and may be revised. 1 2 3 4 The expiry date nobody prints Everything below is current as of this date and no later. Nothing on the page updates itself. Partly a property of the test you ordered VUS rate tracks panel size: 6% on 2–10 gene panels, 76% above 200 genes. A broader test returns more uncertainty, not only more answers. Not a midpoint between benign and pathogenic A statement about the evidence, not about the variant. For management purposes it is an absence of a result — and it is that in both directions. The sentence that tells you what to do Management follows personal and family history, exactly as it would if this line were not on the page.
An illustrative report excerpt. Four elements on the page carry information the classification line itself does not: when the interpretation was fixed, how large a net was cast, what the classification is a claim about, and where management is actually determined.

The guideline is clear; the practice is not

The distance between the rule and the room is well documented. In a survey of women with early-stage breast cancer and their surgeons, 51% of average-risk patients who received a VUS underwent bilateral mastectomy, against 42% of those whose testing found nothing at all. Asked directly, half of lower-volume surgeons and roughly a quarter of higher-volume surgeons said they would manage a patient with a VUS the same way they would manage a carrier of a pathogenic BRCA1 or BRCA2 variant2.

That is not a failure of intelligence. It is what happens when an ambiguous document meets a decision that cannot wait, and nobody in the room has been told which parts of the page are actionable.

What a VUS does and does not support
Action under considerationSupported?
Changing surgical or surveillance management on the strength of the variantNo
Withholding management that the personal or family history would otherwise indicateNo
Testing relatives to determine their riskNo
Targeted family studies coordinated with the laboratory, as evidence to help resolve the variantSometimes
Re-querying the laboratory after an intervalYes

The third and fourth rows are easily confused and are not the same thing. Testing a relative for a VUS tells that relative nothing about their own risk, because the variant's meaning is unknown in anyone who carries it. Segregation studies run through the testing laboratory are a different exercise with a different purpose: they generate evidence about the variant, not risk estimates for the people tested.

The obligation the result actually creates is a date

A classification is a snapshot of the literature and the population databases at the moment the report was issued. It is the only clinical document routinely filed with an implicit expiry and no printed expiry date.

Reclassification is common enough to plan around and lopsided enough to be reassuring. In a large single-laboratory series, 7.7% of unique variants of uncertain significance were reclassified, and 91.2% of those were downgraded to benign or likely benign, with a median of 1.17 years to the amended report3. A multicentre cohort of patients at risk for breast cancer found 20% of VUS reclassified over the study window, at a mean of 2.8 years, with 92% downgraded4. Across germline cancer testing more broadly, something in the range of 6% to 15% of variants are reclassified over five to ten years5.

The direction matters as much as the rate. Most uncertainty resolves toward benign. Waiting is the outcome the evidence favours; acting on the variant is not.

Who tells you when it changes

Frequently, no one — not automatically. ACMG's position is that there is no clear legal duty to re-contact, but that there may be a responsibility, and that the responsibility is shared among the laboratory, the ordering clinician and the patient, with patients expected to make contact periodically to ask whether anything has changed6. Separate guidance addresses when re-evaluation and reanalysis of prior results should be initiated at all7.

In practice, an amended report is issued to an ordering provider who may have changed institutions, and it arrives in a chart that no one has been assigned to read. Survey work found that documenting a patient's re-contact preferences — the step that would make any of this reliable — rarely happens5.

So the obligation a VUS creates is not clinical. It is administrative, and it is the one most often left unowned: somebody has to be responsible for the date.

Some of the uncertainty is about the test, not the patient

Across more than 1.5 million diagnostic tests from 19 laboratories, the proportion of reports carrying at least one VUS was 32.6% for multi-gene panels against 22.5% for exome and genome sequencing — and within panels, the rate tracked panel size closely, from 6.0% for panels of two to ten genes up to 76.2% for panels above 200 genes8. A wider net returns more uncertainty, not simply more answers. A meaningful part of what appears on the page is a consequence of what was ordered.

Ancestry matters too, for a reason that has nothing to do with the patient's biology. Because classification rests on population and case databases that overrepresent people of European ancestry, patients whose ancestry is underrepresented are more likely to receive a VUS: in one cohort assessed with ancestry-informative markers rather than self-report, predominantly East Asian and Middle Eastern genetic similarity were each associated with roughly twice the odds of a VUS result9. The same word on two reports can reflect two different amounts of missing evidence.

What is about to change on the page

In July 2026, ACMG published a statement on how laboratories should report uncertain findings, recommending that they distinguish variants more likely to be reclassified as benign from those where follow-up effort is more likely to be worthwhile — a VUS-low and VUS-high delineation reported transparently rather than held internally10.

If your laboratory adopts it, the single category becomes two, and one useful thing follows: it will not change management, because nothing about a VUS changes management, but it will tell you where chasing resolution is worth the effort. Ask your laboratory whether they are moving to it. The answer tells you something about how much of their internal reasoning you are being shown.

Three questions to ask

  1. To the laboratory: under what circumstances will this variant be re-reviewed, and who receives the amended report?The answer is usually a policy, not a promise, and it usually names the ordering provider rather than the patient or the current care team.
  2. To your own practice: who re-queries this result in two years, and where is that recorded?If the answer is the patient, that is a defensible model — but only if the patient has been told so explicitly and it is documented.
  3. To yourself, before the next decision: would I be doing this if the report had returned nothing?If the answer is no, the variant is driving management, and a variant of uncertain significance is not evidence that can carry that weight.

Zetobit builds and validates clinical bioinformatics pipelines for laboratories, and helps clinical and research teams interpret what their reports and analytical outputs actually establish. If a result in front of you is harder to act on than it should be, that is usually a documentation problem before it is a science problem — and it is a solvable one. contact@zetobit.com

References

  1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424.
  2. Kurian AW, Li Y, Hamilton AS, et al. Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer. J Clin Oncol. 2017;35(20):2232–2239.
  3. Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266–1274.
  4. Reclassification of variants of uncertain significance by race, ethnicity, and ancestry for patients at risk for breast cancer. Front Oncol. 2025;15:1455509. frontiersin.org
  5. Practices and views of US oncologists and genetic counselors regarding patient recontact after variant reclassification: results of a nationwide survey. JCO Precis Oncol. 2023. doi:10.1200/PO.23.00079
  6. David KL, Best RG, Brenman LM, et al. Patient re-contact after revision of genomic test results: points to consider — a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21(4):769–771.
  7. Deignan JL, Chung WK, Kearney HM, et al. Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21(6):1267–1270.
  8. Rehm HL, Alaimo JT, Aradhya S, et al. The landscape of reported VUS in multi-gene panel and genomic testing: time for a change. Genet Med. 2023;25(5):100947.
  9. Ancestry-informative markers and variants of uncertain significance on hereditary cancer panels. Front Oncol. 2026;16:1787278. frontiersin.org
  10. Mighton C, et al. Points to consider for the reporting of variants of uncertain significance in germline genetic and genomic testing: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2026. doi:10.1016/j.gim.2026.102583
Kanna Nandakumar https://www.zetobit.com
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