Rare Genetic Variant Linked to Dramatically Higher Lung Cancer Risk

Lung cancer is commonly associated with tobacco exposure, yet diagnoses among people who have never smoked are increasing, and the contribution of inherited risk remains poorly understood. Because screening pathways rely largely on smoking history, individuals with substantial genetic susceptibility may be overlooked. Large population-scale datasets are now making it possible to better quantify the risks associated with rare inherited variants. A new study shows that the rare inherited EGFR T790M variant is associated with a dramatically increased risk of lung cancer.

Dana-Farber Cancer Institute (Boston, MA, USA), working with the 23andMe Research Institute (Palo Alto, CA, USA), analyzed de-identified, aggregated data to characterize the germline EGFR T790M variant as a major inherited risk factor for lung cancer. The analysis drew on more than 10 million research-consented 23andMe participants, including over 3.3 million with both genetic and lung cancer information. The findings, supported by the INHERIT Study (NCT05587439) in partnership with GO2 for Lung Cancer and the Addario Lung Cancer Medical Institute, were published in Science on September 17, 2026.

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Researchers compared individuals with and without lung cancer to determine whether EGFR T790M was enriched among cases and analyzed never-smokers separately to assess inherited risk independent of tobacco exposure. They also examined associations with 17 other common cancers but found none. Genetic tracing suggested that carriers share an ancestral origin linked to British and Irish settlers, with the variant becoming enriched following a founder event and population bottleneck in Southern Appalachia about 200 years ago.

Overall, EGFR T790M carriers had an approximately 25-fold higher risk of lung cancer than noncarriers. Among never-smokers, carriers were more than 60 times as likely to develop the disease, while risk among smokers was about 10-fold higher. The variant is estimated to occur in roughly 1 in 15,000 people in the United States and as frequently as 1 in 2,000 in parts of the southeastern U.S. Based on these findings, the researchers recommend that people with several family members affected by lung cancer, multiple lung nodules, multifocal lung cancers, or ancestry linked to these regions consider consulting a genetic counselor.

The study highlights how population-scale genetic datasets can uncover high-penetrance cancer predisposition variants and may support future use of genetic testing and tailored screening for people who carry them. Researchers are now working to determine why some carriers develop lung cancer while others do not and how environmental exposures and additional genetic factors may modify risk. Enrollment is continuing in the INHERIT Study, while the Lung Cancer Genetics Study powered by 23andMe is recruiting individuals diagnosed with lung cancer.

"One of the remarkable findings here is just how strong an effect a single mutation can have. To my knowledge, it's one of the strongest, if not the strongest, cancer risk-increasing mutations that has ever been found," said Alexander Gusev, Ph.D., a quantitative geneticist at Dana-Farber Cancer Institute.

"Today, lung cancer screening is driven almost entirely by smoking history. Our findings raise the possibility that, in the future, screening could also be dictated by inherited genetic risk. If further studies confirm the benefit, people with EGFR T790M could be identified through genetic testing and offered personalized CT screening to identify lung cancers when they are at their most curable stage," said Jaclyn LoPiccolo, M.D., Ph.D., attending physician and lung cancer researcher at Dana-Farber Cancer Institute, who co-led the study.

Related Links
23andMe Research Institute
Dana-Farber Cancer Institute