NTHL1 Biallelic gene

Associated Syndrome Name: NTHL1-associated Cancer Risk

NTHL1 Biallelic Summary Cancer Risk Table

Cancer Genetic Cancer Risk
BreastElevated Risk
ColorectalElevated Risk

NTHL1 Biallelic gene Overview

NTHL1-associated Cancer Risk 1, 2, 3, 4, 5, 6
  • Mutations in both copies of the NTHL1 gene (biallelic mutations) have been found in individuals with approximately 10 to 50 colorectal polyps. These polyps are mostly adenomas, which are associated with an increased risk for colorectal cancer. Although there are as yet no precise estimates of the colorectal cancer risk associated with biallelic NTHL1 mutations, it is believed that this risk is significantly increased over that in the general population.
  • Recent studies have found that women with biallelic mutations in NTHL1 have an increased risk for breast cancer, including a possibly increased risk for multiple primary diagnoses. Although there are as yet no precise estimates of this risk, it may be significantly increased over the risk for women in the general population.
  • The small number of individuals identified to date with biallelic NTHL1 mutations have often been diagnosed with other types of cancer as well as colorectal and breast cancer. However, more studies are needed to determine the types of cancer associated with biallelic NTHL1 mutations and the exact size of the risks. At this time there are no professional society guidelines for the management of these additional possible cancer risks.
  • Although there are increased risks for cancer in individuals with biallelic NTHL1 mutations, it may be possible to reduce these risks with appropriate medical management. Guidelines for the medical management of individuals with biallelic NTHL1 mutations have been developed by the National Comprehensive Cancer Network (NCCN). These are listed below. These guidelines will evolve as we learn more, and it is recommended that patients with biallelic NTHL1 mutations be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with hereditary cancer syndromes.

NTHL1 Biallelic gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 803, 5, 7Elevated risk2.8%
Female BreastTo age 806, 7Elevated risk10.6%

NTHL1 Biallelic Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy425 to 30 yearsEvery 2 to 3 years
Colorectal surgical evaluation and counseling.4Based on cancer diagnosis and/or polyp number, size and histologyNA
Female BreastCurrently there are no specific medical management guidelines for female breast cancer risk in biallelic mutation carriers. However, the possibility of an increased risk for breast cancer warrants consideration of individualized breast cancer risk-reduction strategies, such as the modification of standard population screening recommendations by starting screening at younger ages and/or performing screenings at greater frequency.8, 9NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the NTHL1 Biallelic gene.

This patient's relatives are at risk for carrying the same mutation(s) and associated cancer risks as this patient. Cancer risks for females and males who have this/these mutation(s) are provided below.

Family members should talk to a healthcare provider about genetic testing. Close relatives such as parents, children, brothers and sisters have the highest chance of having the same mutation(s) as this patient. Other more distant relatives such as cousins, aunts, uncles, and grandparents also have a chance of carrying the same mutation(s). Testing of at-risk relatives can identify those family members with the same mutation(s) who may benefit from surveillance and early intervention.

Since this patient has mutations in both copies of the NTHL1 gene, it is almost certain each of their parents and all of their children carry at least one of these NTHL1 mutations. Brothers and sisters are at very high risk for carrying either one or two NTHL1 mutations. The cancer risk table that follows provides cancer risks for men and women with mutations in both copies (biallelic) of the NTHL1 gene. These risks do not apply to relatives who have inherited only a single NTHL1 mutation (monoallelic).


  1. Kuiper RP, Nielsen M, De Voer RM, Hoogerbrugge N. NTHL1 Tumor Syndrome. 2020 Apr 2. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. PMID: 32239880.
  2. Weren RD, et al. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018 244:135-142. PMID: 29105096
  3. Belhadj S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin Gastroenterol Hepatol. 2017 15:461-462. PMID: 27720914.
  4. Gupta S, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 1.2021. May 11. Available at https://www.nccn.org.
  5. Kuiper RP, et al. NTHL1 defines novel cancer syndrome. Oncotarget. 2015 6:34069-70. PMID: 26431160.
  6. Grolleman JE, et al. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. Cancer Cell. 2019 35:256-266. PMID: 30753826.
  7. SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute. [Cited 2020 Sep 14]. Available from https://seer.cancer.gov/explorer/.
  8. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. V 1.2022. Aug 11. Available at https://www.nccn.org.
  9. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 1.2021. May 6. Available at https://www.nccn.org.
Last Updated on 20-Jul-2023