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January 07, 2026
4 min read
Key takeaways:
- Prevalence of pathogenic variants in cancer-susceptibility genes appeared independent of personal or family cancer history.
- Broader genetic testing may identify more people at risk and improve early detection.
Up to 5% of Americans may carry genetic variants associated with cancer risk, according to a cross-sectional analysis.
The higher-than-expected prevalence of pathogenic variants in cancer-susceptibility genes — observed independent of family or personal cancer history — underscores how broader genetic testing could identify more people at risk for cancer and lead to earlier detection, researchers concluded.
Data derived from Idumah G, et al. JAMA. 2025;doi:10.1001/jama.2025.16372.
“Ideally, we want to better understand who truly is at risk for cancer from a genetic perspective and who is not, as that can inform decisions about more aggressive screening or strategies designed to prophylactically reduce a person’s risk,” Joshua Arbesman, MD, a dermatologist and physician scientist at Cleveland Clinic, told Healio. “Even with these results, we are not telling everyone to go get genetic testing immediately. However, I think this opens the door for more informed conversations — both with the general population and with people who already had cancer.”
‘Slipping through the cracks’
Germline genetic testing for cancer susceptibility traditionally has been limited to people with established risk factors, such as family or personal cancer history, or a known cancer-causing mutation among a family member.
Several previous studies have examined frequency of pathogenic or likely pathogenic variants among people with cancer, but prevalence in unselected populations had not been well established, according to study background.
Prior research by Cleveland Clinic investigators showed genetic predisposition to melanoma is more than seven times greater than national guidelines estimate. A previous study from another group suggested population-wide prevalence of variants associated with thyroid cancer is up to 20 times greater than current estimates.
In the current study, Arbesman and colleagues aimed to estimate the population-level prevalence of pathogenic or likely pathogenic variants in important cancer susceptibility genes.
The researchers analyzed health records and genetic sequencing data from 414,830 participants in the All of Us research program, an NIH-funded effort that offers one of the world’s largest genomic datasets.
All participants self-reported demographic information — including race, ethnicity and sex — and had short-read whole genome sequencing data available.
Investigators selected 72 common cancer susceptibility genes based off the Invitae Multi-Cancer Panel, designed specifically for heritable germline mutations. They used ClinVar — a free public archive of reports about the relationship between genetic variations and phenotypes — to identify pathogenic and likely pathogenic variants, and they used Systematized Nomenclature of Medicine codes to identify cancer diagnoses.
The analysis identified 3,454 unique pathogenic or likely pathogenic variants spanning 72 genes and 77 transcripts.
These variants occurred among 20,968 unique people, equating to 5.05% of the study sample. About 2.2% (n = 469) of these individuals had variants in two or more genes.
Prevalence of specific genes affected varied, with the three most prevalent being MUTYH (1.33%), BRCA2 (0.42%) and MITF (0.37%).
Prevalence of BRCA2 and BRCA1 (0.22%) exceeded prior estimates among non-Ashkenazi Jewish populations, which range from 0.13% to 0.25%.
“Even when you look at individual genes, the numbers are higher than previously thought,” Arbesman said. “That likely means the criteria we use to recommend genetic testing is missing a certain percentage of people. How many? That is hard to know, but I do think some people are slipping through the cracks.”
Prevalence of pathogenic variants did not differ by ethnicity or sex; however, results revealed significant differences by race. White individuals had the highest prevalence of variants (5.72%) and Asian individuals had the lowest.
Prevalence of 18 genes varied significantly by race, with the most variability reported for MUTYH. Prevalence of variants in 12 genes varied significantly between Hispanic and non-Hispanic members of the cohort.
Carriers of pathogenic/likely pathogenic variants had a higher likelihood of being diagnosed with cancer than noncarriers (26.4% vs. 19.7%). They also were younger at the time of first cancer diagnosis (mean age, 56.9 years vs. 59 years; median age, 58.6 years vs. 60.9 years) and more likely to have at least one family member with cancer (70.1% vs. 64.9%).
Age at first cancer diagnosis differed by gene, with the lowest median age reported for carriers of STK11 (31.4 years) and DICER1 carriers (35.4 years) and the highest median age reported for AIP carriers (70.8 years).
‘Knowledge is powerful’
Arbesman and colleagues acknowledged study limitations.
Although their study included a more diverse population and greater representation of historically underrepresented groups than most prior genomic research, the sample was not “demographically representative” of the national population, they wrote.
Voluntary study participation could introduce healthy volunteer bias, and self-identified ethnicity and race may not entirely capture genetic ancestry, they added.
Analysis of other datasets will be essential to validate the findings, Arbesman said, as will improved understanding of what specific genetic alterations mean from a disease process standpoint.
“I also can say with relative certainty that there likely are more genes that we don’t know about that are relevant to cancer susceptibility,” Arbesman said. “Further follow-up studies on that aspect will be necessary.”
Although current guidelines for genetic testing may not be adequate to identify all individuals at elevated risk for cancer due to genetic variants, the clinical impact of broader screening has not been assessed. Additional research is necessary to determine its feasibility, clinical utility and cost-effectiveness, Arbesman said.
“Infrastructure is always a consideration,” Arbesman said. “Do we have enough genetic counselors? What about the costs? In this case, testing may save money in the long run, because the cost of treating late-stage disease is much greater than the cost of genetic testing.”
Educating the general population and the clinical community about higher-than-expected prevalence of variants in cancer susceptibility genes and the potential benefits of genetic testing will be important, Arbesman said.
“I’m not advocating for population-based screening, but we can do more,” he said. “At one time, genetic testing was much more expensive and labor intensive. A person could be told they were at risk for cancer even though we couldn’t do anything about it, and testing without intervention fuels anxiety.
“Now, we have cheaper and better testing, as well as measures we can pursue to help people at risk be more proactive,” Arbesman added. “For a lot of people, knowing they are at risk for a particular cancer, or perhaps multiple cancer types, can be life altering in a positive way. That knowledge is powerful, both psychologically and health-wise, if they follow recommendations for lifesaving cancer screening and seek other appropriate care. We need to get that message out.”
For more information:
Joshua Arbesman, MD, can be reached at arbesmj@ccf.org.
Sources/Disclosures
Source:
Idumah G, et al. JAMA. 2025;doi:10.1001/jama.2025.16372.
References:
Disclosures:
Arbesman reports personal fees from Disc Medicine; grants from Castle Biosciences, Celldex, Clinuvel and Variant Bio; and stock ownership in Sanotize. The other authors report no relevant financial disclosures.
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