Pathogenic variants (disease-causing) in both copies of the MLH3 gene have MLH3-associated polyposis syndrome, which is associated with an increased risk of colorectal polyps and colorectal cancer. Published data show that the MLH3 gene can produce non-colon tumors, but the exact lifetime risk numbers are not well defined because this condition is rare. Management of MLH3–related tumor risk includes regular surveillance tailored to guidelines to detect tumors early. MLH3 variants are not known to be more common in the Ashkenazi Jewish population.
As noted above, MLH3-associated polyposis exhibits autosomal recessive inheritance. This means that both parents must be carriers of an MLH3 pathogenic variant to have a 25% chance to have a child with the condition; a carrier means that an individual has a single MLH3 pathogenic variant. Carriers, to the best of our knowledge, do not have an increased of cancer or polyps. If an individual has MLH3-associated polyposis, the chance their children could have it depends on the genetic make-up of the other parent.
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Written December 2025
