In addition to today’s resource, please see Research Letter
Pathogenic Germline Variants in Cancer Susceptibility Genes [Full-Text HTML].
Gideon Idumah, PhD1; Daphne Newell, BS2; Madeleine Hadrys3 et al. JAMA
Published Online: October 16, 2025. 2025;334;(19):1765-1768. doi:10.1001/jama.2025.16372 This article is what is discussed in the Medscape article below.
There are 101 similar articles in PubMed. The above article has been cited by 9 articles in PubMed.
Today, I review, link to, and excerpt from Medscape News‘ “Unselected Screening Uncovers Hidden Cancer Genetics”. Maurie Markman, MD, October 23, 2026.
All that follows is from this resource.
[Please review the 4:45 video on the above link by Dr. Markman.]
This transcript has been edited for clarity.
Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss a very interesting, provocative analysis and a little bit about the potential implications for what these authors suggest. The paper is “Pathogenic Germline Variants in Cancer Susceptibility Genes,” published in JAMA.
It’s increasingly recognized that the germline is responsible for the increased risk for cancer in a number of very relevant syndromes. Obviously, the medical community — and increasingly the public — is aware of the association of BRCA1 and BRCA2, for example, in breast cancer, ovarian cancer, prostate cancer, pancreas cancer, and other abnormalities, including the genetic abnormalities associated with Lynch syndrome.
Article Key Points
- 414,830 unselected adults underwent short-read whole-genome sequencing.
- 5.05% had pathogenic/likely pathogenic germline variants.
- 20,986 individuals carried 3,454 unique variants across 72 genes.
- BRCA1/2 variants were more frequent than prior smaller studies predicted.
- Population screening may alter cancer risk stratification; cost-effectiveness unresolved.
Dive Deeper [Links to Dive Deeper are in the article}Which cancer susceptibility genes are most prevalent in population screening?How accurate is family history for detecting germline cancer risk?What is the cost-effectiveness of universal germline screening?The question that the investigators in this study proposed was somewhat different: Yes, we know about these syndromes, we’ve found high risk in certain populations — for example, BRCA abnormalities in the Ashkenazi Jewish population. How common are these pathogenic germline variants within the general population that doesn’t have knowledge of their presence, and do we adequately capture this risk by our standardized methods, such as taking a family history of cancer?
What we’re looking at here is data from the All of Us study, which enrolled US participants regardless of health status. A total of 414,830 individuals had short-read whole-genome sequencing performed. They also had self-reported demographic information provided. Cancer susceptibility of the germline was based on the Invitae Multi-Cancer Panel, and pathogenic or likely pathogenic variants were identified using ClinVar.
The bottom line here was that this analysis identified 3454 unique pathogenic or likely pathogenic variants across 77 different transcripts in 72 genes in a total of 20,986 unique individuals, representing — and I’ll say this twice — 5.05% of the total population. Five percent. One out of 20 healthy individuals who were screened as part of this, 5%, had a pathogenic or likely pathogenic germline variant.
This is obviously highly provocative data. In fact, if one looked at the BRCA1 or BRCA2 incidence in this population, it was higher in this unselected population than would have been predicted based upon much smaller studies.
What are the public health and individual health implications? One could ask, for example, if we had this information at a population level on individuals, might we potentially modify our screening strategy for breast cancer or other cancers to focus on these individuals with higher risk and potentially also prevention strategies, modifications of diet, etc., based on that?
Again, no answers came out of this analysis. It’s complicated. There would obviously have to be a detailed economic analysis of the value of this approach, but it raises an important question. These abnormalities are not rare in any circumstance, at 5% in this population-based study. Clearly, there is much more to discuss and to talk about in the future.
I thank you for your attention.
