Charna Albert
September 2026—When Heidi Rehm, PhD, and other researchers examined more than 1.5 million diagnostic sequencing test results from 19 clinical laboratories, they found an astonishing rate of inconclusive reports due to variants of uncertain significance—nearly a third in diagnostic multigene panel testing.
The historical reason for reporting VUS in diagnostic testing was to allow physicians to conduct follow-up on variants that might be causal. But as multigene panels have grown to include more genes and a broader range of clinical indications, VUS have become more prevalent and less likely to be related to patient symptoms. Current reporting practices, Dr. Rehm and her coauthors wrote in 2023, have not evolved to keep pace with the higher likelihood of identifying uncertainty (Rehm HL, et al. Genet Med. 2023;25[12]:100947).
A new guidance statement of the American College of Medical Genetics and Genomics takes a first step. It addresses the need for test reporting that identifies test scenarios that should not include any VUS, and other scenarios that need to emphasize VUS more likely to be causal and deemphasize VUS with little evidence of pathogenicity (Mighton C, et al. Genet Med. 2026;28[7]:102583). “We recognize the enormous challenge to laboratories, patients, and the physicians who are managing these reports,” says Dr. Rehm, coauthor and professor of pathology at Harvard Medical School.
The statement precedes the forthcoming ACMG/AMP/CAP/ClinGen standards for sequence variant classification (SVC v4.0), likely to be published early next year. SVC v4.0 will replace the 2015 framework for interpreting sequence variants with a points-based system for dividing VUS into subclasses by likelihood of pathogenicity.
“We wanted to give the community guidance on how to use these subclasses in reporting,” says Dr. Rehm, chief genomics officer at Massachusetts General Hospital and co-director of medical and population genetics at the Broad Institute. “But also, we recognized there wasn’t comprehensive guidance around when and when not to report VUS across different clinical areas of testing.” The statement, she says, addresses the need for more direction on VUS reporting and aims to unify laboratories under a clear set of protocols. “There were different practices across different areas of testing, and we wanted to create consistency,” Dr. Rehm says.
Variants of uncertain significance are also a source of frustration for patients.
In a study that surveyed patients with cancer on their views of low-risk results from genomic sequencing and whether they preferred to be informed about variants of uncertain significance, one participant memorably said, “I don’t need any more unknowns hanging over my head.” Findings that led to specific clinical follow-up, on the other hand, such as low/moderate risk breast cancer genes, were perceived as useful and reassuring (Shickh S, et al. Genet Med. 2023;25[12]:100960).
“There are benefits and risks to reporting VUS,” Dr. Rehm says. The hope is that through reporting, new evidence of pathogenicity will be generated. “You can’t just say, ‘We’ll only report pathogenic variants to patients, and we’ll wait until variants become pathogenic to consider reporting them.’” If they go completely unreported, “most will never build evidence and no one will benefit.”
Also true: Of the VUS that change classification, 80 percent move to benign. Moreover, she says, the prior probability a variant is pathogenic is much higher in the symptomatic testing context versus the asymptomatic.
All the more reason to prioritize those with some prior evidence to suggest investigation will lead to a causal finding.
“We wanted to put out specific guidance to help people think about the rationale for why we’re reporting VUS and emphasize the contexts in which it is optimal versus not optimal, as you balance the risk-to-harm ratio,” she says.
One key point that does not depart from current genetic testing laboratory practice: If testing is for a symptomatic patient, report VUS. If asymptomatic, do not report VUS.
For symptomatic testing, the statement adds, this guidance should be followed in all testing contexts, including preimplantation, prenatal (excluding cell-free fetal DNA screening), perinatal, pediatric, adult, and postmortem. Asymptomatic testing applies to return of secondary or incidental findings, population testing, newborn sequencing, pharmacogenomic testing, prenatal and preconception carrier screening, and prenatal genetic and genomic testing.
The guidance recognizes, however, that some organizations have more familiarity with genetic testing and more capacity to educate patients. “Most physicians are not equipped to deal with VUS” and all that proper management entails, including consent and pretest counseling, Dr. Rehm says. “But we recognize there are nuanced situations. If you have the capacity to thoroughly consent and discuss the benefits and risks of returning these results to a family and you’re prepared to counsel them appropriately,” it might be acceptable to return VUS in certain asymptomatic contexts, “or not return the VUS in sympto-matic testing because the family didn’t want to deal with uncertainty.”
“We talked at length about the exceptional scenarios,” she adds, “but we also wanted to continually balance and give general guidance that was pragmatic for laboratories, recognizing the limited resources they have and the lack of direct interaction with patients.”
The recommendation to not report VUS in asymptomatic prenatal testing may be a departure from current laboratory practice and was the subject of debate among the working group that developed the guidance. External experts were brought in on this topic, and community member feedback was provided via a survey.
“Historically it had been acceptable to return [VUS] results from cytogenomic microarray testing and, prior to that, karyotyping,” Dr. Rehm says. But older prenatal testing technologies had lower resolution than current technologies. “Most of the time you were finding large chromosomal abnormalities,” she says, whereas newer methods identify smaller copy number and structural variants that are more likely benign. And in most cases, identifying a symptomatic phenotype isn’t possible in utero. (“How can you assess the symptoms in a fetus?”) Additional guidance from the ACMG for prenatal variant reporting is forthcoming and should better delineate and standardize reporting practices, Dr. Rehm and her coauthors write.
The recommendations for cancer testing, too, were challenging to delineate. “There are people getting tested who may have symptoms or may have a family history, but in general the likelihood of finding a hereditary cause of cancer is quite low because cancer is a common nongenetic finding, as well as the small percentage that are hereditary. And so managing this as a symptomatic/asymptomatic test is challenging,” she says.
Their solution was to suggest laboratories offer cancer screening panels in two versions: one a risk test in which VUS are not included in the report, and the other a symptomatic test in which VUS are reported. Physicians can use their judgment on which to order based on the patient’s symptoms, family history, and likelihood of a genetic etiology. Crucially, this skirts the need for custom reports. “That would be a burden for laboratories to manage, so we suggested it be done at the test order level,” she says.
When a report harbors a VUS, a laboratory might suggest further investigation—parental testing to determine de novo occurrence, for example, or segregation testing in affected and unaffected family members.
At least some of this work, the data suggests, does not lead to answers for the patient.
In a study of four clinical laboratories that for a decade or more have stratified VUS by the subclasses that will be introduced by SVC v4.0, Dr. Rehm and her coauthors examined the composition of each laboratory’s VUS subclasses and the likelihood that variants from each subclass were reclassified toward pathogenic or benign. The subclasses used by the four laboratories included VUS-low (evidence to suggest the variant may be benign), VUS-mid (equivocal), and VUS-high (evidence to indicate the variant is more likely to become pathogenic) (Bennett G, et al. Genet Med. 2025;27[6]:101400).
Of the 151,368 variants included in the study, just four percent were classified as VUS-high. “It’s a small fraction, and of those that got reclassified, half moved to pathogenic,” Dr. Rehm says. In contrast, variants in the VUS-low category never moved to the pathogenic/likely pathogenic classification. “We made the argument that by asking laboratories to put the subclassification on the report, we could allow physicians to focus on added effort in just a small subset of variants.”
Dr. Rehm and her coauthors found that when variants changed classification or subclassification, they were 4.3 times more likely to move down toward benign rather than up toward pathogenic. “Today there’s a lot of work that goes into investigating VUS, most of which will become benign,” she says. “So in our view, while we are encouraging follow-up,” such as parental testing, “focus those efforts on VUS-high. That will decrease the total number of VUS you need to follow up on and increase the likelihood that work leads to diagnostic outcome.”
“We weren’t prescriptive,” Dr. Rehm says, about how reporting should emphasize variants likely to be causal and deemphasize those more likely to be benign. “We understand labs have constraints around report formats based on the software systems they use to write reports,” she says. Including VUS subclasses in the report will help. “But they could also put the VUS-low in an appendix or a supplement at the end of the report,” she says. “Whereas today, a patient sees a VUS and they think, ‘This could be my cause.’ And a fair number of physicians assume the lab is being cautious and that the variant is causal. There are huge errors there.”
The four laboratories Dr. Rehm and her coauthors studied—Mass General Brigham Laboratory for Molecular Medicine, Baylor Genetics, Labcorp, and Quest Diagnostics—each took a distinct approach to VUS subclasses. “Labcorp never put the subclasses on the report; it was just used for internal purposes,” she says. Baylor implemented the subclasses at the request of physicians who wanted to reduce VUS on cancer reports. “They implemented the VUS-low category to prevent putting those variants in the report,” she says. Quest used a visualization to demonstrate where VUS fell in terms of risk. The laboratory at Mass General, which Dr. Rehm once led, used on its report the written terms “VUS favor benign” and “VUS favor pathogenic.”
But while the terminology and use varied among the four laboratories, all received positive feedback from clinicians, who found the subclasses helped set expectations with patients. “They could say, ‘This variant is most likely to move to benign, or [with] this variant, there’s a reasonable chance we could discover this is causal later—you should follow up with me regularly about this variant.’”
Patient reports should be updated when variants are reclassified, the guidance says. “Most major laboratories do this already,” she says, though not necessarily for every change. The Mass General laboratory she led would issue an update for variants that moved to pathogenic or likely pathogenic and therefore came with a new diagnosis. Common changes, like VUS to likely benign, wouldn’t get an update. “Our main approach for that was to submit all our variants on a regular basis to ClinVar,” the free public archive of reports of human variations. Patients, too, she notes, can choose to follow a particular variant in ClinVar and get notified of changes in status.
Because not every laboratory has an automated system for delivering updates, the guidance allows some flexibility, she says. Unexpected changes like pathogenic (P)/likely pathogenic (LP) or benign (B)/likely benign (LB) variants that move to VUS or further, such as P/LP to B/LB or vice versa, are the highest priority for updated reporting. Second priority are variants that move from VUS to P/LP, third are those from VUS to B/LB, and lowest are variants moving within a category (between VUS subclasses or LP to P or LB to B). “There are different ways this is handled, and we acknowledge that depending on the amount of automated support for this, how much updating happens may vary,” Dr. Rehm says. “As systems become more automated, there could be an expansion of the number of types of updates that could be conveyed.”
Although not all VUS should be reported to patients, laboratories should share knowledge of variants observed and interpreted during testing through submission to ClinVar and other methods, the statement notes.
More laboratories are now sharing this information, Dr. Rehm says. Still, important data is often left out.
“It’s useful to see what a laboratory is saying about a variant, but what we really need is access to the underlying evidence for why a laboratory called a variant pathogenic or benign,” she explains. Patient privacy is a concern. “Because these patients aren’t consented for very detailed data sharing, particularly in a public database, the details of the case—such as detailed phenotype, age, and other variants identified—are rarely shared in those ClinVar entries,” she says.
The missing details are sometimes disclosed in behind-the-scenes communications, she says. When a laboratory submits a variant to ClinVar, they may see it has been reported by other laboratories and contact those laboratories for further information. “We’ve had incredibly rich exchanges and, in many cases, that has allowed for a change in the variant classification. But those are labor-intensive exchanges. And especially if you’re a large submitter to ClinVar, it’s difficult to support the number of inquiries coming in,” she says.
She and her colleagues are working on a solution. “We call it federated variant level matching (VLM), where we can connect rare disease genomic data sets in a federated network and be able to query on a per-variant basis and enable access to individual-level phenotypes in a secure manner,” she says.
If she could snap her fingers and make one change to the way data sharing occurs now? “It would be to connect every genomic data store to this system and allow data exchange at a scale we’ve never experienced before, especially from the clinical labs.”
The need for data sharing goes beyond the U.S. “It’s not equal in terms of what’s happening in the U.S. versus around the world. We’re working closely with many labs around the world to encourage broader adoption of ClinVar submission and now participation in the federated VLM network.”
Better representation of genetic diversity in genomic research is yet another piece of the puzzle.
Among genetic ancestry groups underrepresented in genomic research, VUS rates are higher and positive diagnostic findings lower. Worldwide population data sets and equitable testing of all individuals with rare disease are needed, and she oversees with others the gnomAD database, composed of global exome and genome sequences. “Still, a huge fraction of it is of European ancestry,” she concedes. “And when we’re trying to filter genomes and get rid of common variants so we can focus in on a small subset of variants that might be causal, it is hugely beneficial to have population allele frequencies from every population, because certain variants may be absent or rare in one population but common in another.” Looking at those commonalities, “we can further reduce the number of variants that we’re trying to interpret for causes of rare disease. So general population sharing through large biobank and genomic population sequencing efforts is critical.”
Through gnomAD, she and others are working on a multi-country effort to improve representation and diversity in population data sets, in which countries around the world process their raw genomic data and send to gnomAD the aggregate allele frequencies. These can be shared, she says, “because it’s no longer individual-level data.”
With most causal variants private to families or present in a small number of families, diversity in research is even more essential, she says.
“If you’re not doing rare disease testing or research studies in every population, you’re not generating the cases and evidence to understand all causes of rare disease.”
Charna Albert is CAP TODAY senior editor.