Pathogenic variants (disease-causing) in both copies of the NTHL1 gene cause NTHL1 tumor syndrome, a rare autosomal recessive condition associated with an increased risk for multiple types of cancer. Individuals with two NTHL1 variants often develop multiple colorectal polyps and have an increased lifetime risk for colorectal cancer, breast cancer, and endometrial (uterine) cancer. Additional cancers have been reported in some individuals, but the full spectrum and exact lifetime risks remain uncertain because the condition is rare. Management of NTHL1–related tumor risk includes regular surveillance tailored to guidelines to detect tumors early. NTHL1 variants are not known to be more common in the Ashkenazi Jewish population.
As noted above, NTHL1 tumor syndrome exhibits autosomal recessive inheritance. This means that both parents must be carriers of an NTHL1 pathogenic variant to have a 25% chance to have a child with the condition; a carrier means that an individual has a single NTHL1 pathogenic variant. Carriers, to the best of our knowledge, do not have an increased of cancer or polyps. If an individual has NTHL1 tumor syndrome, the chance their children could have it depends on the genetic make-up of the other parent.
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Written December 2025
