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NTHL1 Tumor Syndrome

Synonym: NTHL1-Associated Polyposis

, PhD, , MD, PhD, , MD, , PhD, and , MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: March 20, 2025.

Estimated reading time: 24 minutes

Summary

Clinical characteristics.

NTHL1 tumor syndrome is characterized by an increased lifetime risk for colorectal cancer (CRC), breast cancer, and colorectal polyposis. Colorectal polyps can be adenomatous, hyperplastic, and/or sessile serrated. Duodenal polyposis has also been reported. Additional cancers reported in individuals with NTHL1 tumor syndrome include endometrial cancer, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies. The cumulative lifetime risk of developing extracolonic cancer by age 60 years has been estimated at 35% to 78%.

Diagnosis/testing.

The diagnosis is established in a proband by identification of germline biallelic pathogenic variants in NTHL1 by molecular genetic testing.

Management.

Treatment of manifestations: Colorectal polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point, either subtotal colectomy or proctocolectomy is performed based on polyp features and location. Large duodenal polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Surveillance: Colonoscopy every two years beginning at age 18-20 years; breast MRI examination annually in females between ages 30 and 60 years; mammography annually in females between ages 40 and 50 years, then every two years between ages 50 and 75 years; transvaginal ultrasound and endometrial biopsy every two years in females between ages 40 and 60 years may be considered depending on local guidelines for endometrial cancer surveillance; esophagogastroduodenoscopy at least every five years beginning at age 25 years; brain MRI for meningioma at diagnosis with follow-up imaging in those with signs and/or symptoms of meningioma.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual who has germline biallelic NTHL1 pathogenic variants in order to identify as early as possible those who would benefit from appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Genetic counseling.

NTHL1 tumor syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NTHL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the NTHL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Diagnosis

Formal diagnostic criteria for NTHL1 tumor syndrome have not been established.

Suggestive Findings

NTHL1 tumor syndrome should be suspected in an individual with the following clinical findings, family history, and/or molecular genetic findings on tumor tissue.

Clinical findings

  • Presence of multiple primary cancers before age 50 years, especially breast, colon, or urothelial cell cancer, meningiomas, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma
  • Colorectal cancer (CRC) diagnosed before age 40 years
  • One or more colorectal adenomas in an individual age ≤40 years
  • A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
  • A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age

Family history is consistent with autosomal recessive inheritance of multiple cancers (especially breast, colorectal, or urothelial cell cancer, brain tumors, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma).

Molecular genetic findings on tumor tissue. A specific mutational signature due to a high percentage of somatic C>T transversions (e.g., COSMIC Signature 30) is identified on tumor tissue testing [Grolleman et al 2019].

Establishing the Diagnosis

The diagnosis of NTHL1 tumor syndrome is established in a proband with biallelic germline pathogenic (or likely pathogenic) variants in NTHL1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic NTHL1 variants of uncertain significance (or of one known NTHL1 pathogenic variant and one NTHL1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When phenotypic findings suggest the diagnosis of NTHL1 tumor syndrome, molecular genetic testing approaches can include use of a multigene panel or single-gene testing.

  • A CRC and polyposis multigene panel that includes NTHL1, APC, MUTYH, and other genes of interest (see Differential Diagnosis) is most likely to identify NTHL1 tumor syndrome while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) Given the rarity of NTHL1 tumor syndrome, some cancer predisposition multigene panels may not include NTHL1. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Single-gene testing. Sequence analysis of NTHL1 detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Sequence analysis of all six exons of NTHL1 is recommended. To date, no large exon or whole-gene deletions or duplications in NTHL1 have been reported, but their contribution to NTHL1 tumor syndrome cannot be excluded. Therefore, copy number analysis is recommended, particularly when only one germline NTHL1 pathogenic variant has been identified in an individual with findings suggestive of NTHL1 tumor syndrome.

Option 2

When the diagnosis of NTHL1 tumor syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, NTHL1 pathogenic variants reported (e.g., frameshift, nonsense, and splice site) are within the coding region and canonical splice site regions and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in NTHL1 Tumor Syndrome

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
NTHL1 Sequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5None reported 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

Clinical Characteristics

Clinical Description

NTHL1 tumor syndrome has been described in 50 families with 72 affected individuals [Rivera et al 2015, Weren et al 2015, Chubb et al 2016, Belhadj et al 2017, Broderick et al 2017, Buchanan et al 2017, Fostira et al 2018, Altaraihi et al 2019, Belhadj et al 2019, Grolleman et al 2019, Groves et al 2019, Heald et al 2019, Terradas et al 2019, Boulouard et al 2021, Liu et al 2021, Opalič et al 2021, Esnakula et al 2022, Wakeling et al 2022, Pinto et al 2023, Weatherill et al 2023, Terlouw et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Colon polyps. Of the 40 individuals reported by Beck et al [2022] who had been evaluated by colonoscopy, all but two were found to have adenomatous polyps (range: 2-150). In addition, several individuals were reported to have had hyperplastic/sessile serrated polyps [Grolleman et al 2019].

Colorectal cancer (CRC). Thirty-seven of 72 individuals reported to date developed CRC. The median age of onset was 51 years (range: 31-73 years). Nineteen individuals were diagnosed with CRC before age 50 years [Rivera et al 2015, Weren et al 2015, Chubb et al 2016, Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019, Boulouard et al 2021, Beck et al 2022, Esnakula et al 2022, Wakeling et al 2022, Pinto et al 2023, Weatherill et al 2023, Terlouw et al 2024]. CRC in individuals with NTHL1 tumor syndrome was mostly right-sided, but has been observed throughout the colon, from the rectum to the appendix [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019, Terlouw et al 2024]. Metachronous or synchronous tumors were identified in at least nine individuals [Fostira et al 2018, Grolleman et al 2019, Wakeling et al 2022, Weatherill et al 2023, Terlouw et al 2024]. The limited number of families and the presence of a selection bias in the individuals reported to date hamper accurate cancer risk analysis. In the absence of timely surveillance, the lifetime risk for CRC in individuals with NTHL1 tumor syndrome is likely to be high.

Breast cancer has been observed in 12 of 22 females with NTHL1 tumor syndrome with a median age of onset of 49 years (range: 36-63 years) [Beck et al 2022]. At least three had bilateral breast cancer. The reported subtypes included ductal, lobular, and mixed ductal/papillary. Hormone receptor status (triple negative) was reported in one individual. One male was reported with breast cancer [Esnakula et al 2022].

Endometrial cancer has been diagnosed in five of 22 females with NTHL1 tumor syndrome, with a median age of diagnosis of 57 years (range: 47-74 years) [Grolleman et al 2019, Beck et al 2022].

Duodenal polyps and cancer. Multiple duodenal polyps were reported in two individuals with NTHL1 tumor syndrome [Weren et al 2015, Fostira et al 2018]. One individual also developed esophageal polyps. Two individuals developed duodenal cancer [Weren et al 2015, Boulouard et al 2021]. However, one individual with duodenal cancer also presented with a heterozygous germline pathogenic variant in MSH2 [Boulouard et al 2021, Beck et al 2022].

Meningiomas. To date, 11 meningiomas have been reported in individuals with NTHL1 tumor syndrome (10 females, 1 male) with a median age of onset of 46 years (range: 37-64 years) [Rivera et al 2015, Weren et al 2015, Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019, Boulouard et al 2021, Liu et al 2021, Esnakula et al 2022, Weatherill et al 2023].

Other cancers. Additional cancers reported in individuals with NTHL1 tumor syndrome include urothelial carcinoma of the bladder, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019, Beck et al 2022]. Grolleman et al [2019] reported the presence of multiple primary tumors in 16 of 29 individuals (55%). Based on these findings, the cumulative lifetime risk of developing extracolonic cancer by age 60 years was estimated at 35% to 78% (95% CI) [Grolleman et al 2019].

Benign extraintestinal manifestations reported in some individuals include skin hemangiomas, seborrheic keratosis, and intradermal nevi; ovarian and hepatic cysts; and breast papillomas. To date, the number of individuals reported with these features is low and an association with NTHL1 tumor syndrome is unclear.

NTHL1 heterozygotes. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A low-to-moderate increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023]. A previously reported individual with breast cancer had a germline heterozygous NTHL1 variant (NM_002528.6:c.859C>T [p.Gln287Ter]) and loss of heterozygosity in tumor tissue [Nik-Zainal et al 2016, Drost et al 2017].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Nomenclature

This condition has been referred to as NTHL1 polyposis and familial adenomatous polyposis 3 (OMIM 616415), a term that emphasizes the similarity with MUTYH polyposis [Belhadj et al 2017, Groves et al 2019, Valle et al 2019]. Considering the broad tumor spectrum reported in individuals with biallelic NTHL1 pathogenic variants and the fact that the diagnosis has been identified in individuals without CRC and/or (suspected) polyposis, the term NTHL1 tumor syndrome is preferred.

Prevalence

The prevalence of NTHL1 tumor syndrome is unknown. Based on the prevalence of NTHL1 pathogenic variants in the population, it has been estimated that in Europeans, NTHL1 tumor syndrome would occur with a frequency approximately one fifth (1:114,770) that of MUTYH polyposis (1:19,079) [Weren et al 2018].

Differential Diagnosis

Genes of interest in the differential diagnosis of NTHL1 tumor syndrome are listed in Table 2.

Table 2.

Genes of Interest in the Differential Diagnosis of NTHL1 Tumor Syndrome

Gene(s) 1MOIDisorderClinical Features of Disorder
Overlapping w/NTHL1 tumor syndromeDistinguishing from NTHL1 tumor syndrome
MBD4 ARTumor predisposition syndrome 2 (OMIM 619975)
  • ↑ CRC risk
  • 10-100 adenomas
  • Uveal melanomas
  • Acute myeloid leukemia
MSH3 ARFamilial adenomatous polyposis 4 (OMIM 617100)
  • ↑ CRC risk
  • 10-100 adenomas
  • Duodenal adenomas
  • Breast cancer in 1 female
Liver cyst in 3 sibs 2
MUTYH AR MUTYH polyposis
  • ↑ CRC risk
  • Usually 10-100 adenomas
  • Serrated polyps also observed
  • Duodenal adenomas
↑ risk of ovarian, endometrial, bladder, skin, & thyroid cancer has been reported, but more evidence is needed.
APC ADAttenuated familial adenomatous polyposis (See APC-Assoc Polyposis Conditions.)
  • ↑ CRC risk
  • Average of 30 colonic polyps
  • Duodenal adenomas
Extracolonic manifestations (e.g., desmoid tumors, fundic gland polyps, congenital hypertrophy of retinal pigmented epithelium, dental abnormalities, fibromas, & osteomas)
BMPR1A
SMAD4
AD Juvenile polyposis syndrome ↑ CRC risk
  • GI hamartomatous (juvenile) polyps
  • ↑ risk of cancers of upper GI tract & pancreas
  • Hereditary hemorrhagic telangiectasia (SMAD4-related)
EPCAM
MLH1
MSH2
MSH6
PMS2
AD Lynch syndrome
  • ↑ CRC risk
  • Endometrial cancer
  • Usually <10 adenomas
  • ↑ risk for ovarian cancer
  • Sebaceous skin tumors
  • Mismatch repair-deficient tumors
15q13-q14 duplication (upstream of GREM1)ADHereditary mixed polyposis syndrome (OMIM 601228)
  • Adenomatous polyps
  • ↑ CRC risk
Mixed polyposis (hyperplastic, atypical juvenile, & adenomatous polyps)
POLD1 ADCRC, susceptibility to, 10 (OMIM 612591)
  • 10-100 adenomas
  • ↑ CRC & endometrial cancer risk
Astrocytoma risk
POLE ADCRC, susceptibility to, 12 (OMIM 615083)
  • 10-100 adenomas
  • ↑ CRC, ureter cancer, & endometrial cancer
↑ risk for ovarian cancer, gastric cancer, & astrocytoma
PTEN AD PTEN hamartoma tumor syndrome ↑ CRC, breast cancer, & endometrial cancer risk
  • Multiple hamartomatous & mixed polyps in GI tract
  • Macrocephaly, lipomas of skin, & multinodular goiter
  • ↑ risk for melanomas, thyroid cancer, & renal cancer
STK11 AD Peutz-Jeghers syndrome ↑ CRC & breast cancer risk
  • GI hamartomatous polyps, most often in small bowel
  • Typical mucocutaneous pigmentation
  • ↑ risk for lung, gastric, pancreas, & sex organ cancers
TP53 AD Li-Fraumeni syndrome ↑ CRC & breast cancer risk↑ risk for sarcoma, lung cancer, adrenocortical carcinoma, choroid plexus carcinoma, & additional cancers

AD = autosomal dominant; AR = autosomal recessive; CRC = colorectal cancer; GI = gastrointestinal; MOI = mode of inheritance

1.

Listed by mode of inheritance, then alphabetically by gene.

2.

Management

No clinical practice guidelines for NTHL1 tumor syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NTHL1 tumor syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

NTHL1 Tumor Syndrome: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Colon polyps / CRC ColonoscopyBeginning at age 18-20 yrs
Breast cancer Breast MRI 1Beginning at age 30 yrs
MammographyBeginning at age 40 yrs
Endometrial cancer Transvaginal ultrasound exam & endometrial biopsy 2Beginning at age 40 yrs
Duodenal polyps / cancer Upper endoscopyBeginning at age 25 yrs
Meningioma Brain MRIAt time of diagnosis
Genetic counseling By genetics professionals 3To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of NTHL1 tumor syndrome to facilitate medical & personal decision making

CRC = colorectal cancer; MOI = mode of inheritance

1.

Breast MRI sensitivity is greater than that of mammography.

2.

Evaluation may be considered in centers that recommend surveillance for endometrial cancer.

3.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4). In general, the treatment regarding gastrointestinal tumors is similar to that of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (see APC-Associated Polyposis Conditions).

Table 4.

NTHL1 Tumor Syndrome: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Colon polyps / CRC
  • Polyp resection during colonoscopy
  • When colonoscopy w/polypectomy can no longer manage the large size & density of polyps, subtotal colectomy or proctocolectomy is performed based on polyp features & location. 1
Breast cancer Standard treatments
Endometrial cancer
Duodenal polyps / cancer
  • Mgmt of polyps is similar to that in persons w/FAP; large polyps should be excised during endoscopy.
  • Standard treatments

CRC = colorectal cancer; FAP = familial adenomatous polyposis

1.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Table 5.

NTHL1 Tumor Syndrome: Recommended Surveillance

ConcernEvaluationFrequency
Colon polyps / cancer ColonoscopyEvery 2 yrs starting at age 18-20 yrs
Breast cancer Breast MRI 1In females: annually between ages 30 & 60 yrs
MammographyIn females: annually between ages 40 & 50 yrs; every 2 yrs between ages 50 & 75 yrs
Endometrial cancer Transvaginal ultrasound & endometrial biopsy 3In females: every 2 yrs between ages 40 & 60 yrs
Duodenal polyps / cancer EsophagogastroduodenoscopyAt least every 5 yrs starting at age 25 yrs
Meningioma Brain MRIIn those w/concerning clinical sign/symptoms
1.

Breast MRI sensitivity is greater than that of mammography for detecting breast cancer.

2.

Frequency per Spigelman criteria [Spigelman et al 1989]

3.

May be considered depending on local guidelines for endometrial cancer surveillance

Individuals heterozygous for a germline NTHL1 pathogenic variant. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A small increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023]. There are no specific screening recommendations for heterozygous relatives of individuals with NTHL1 tumor syndrome. NTHL1 heterozygotes are advised to participate in population screening measures for colorectal cancer (CRC) and breast cancer or could be offered screening based on their family history (e.g., incidence of CRC and/or breast cancer in family members who do not have biallelic NTHL1 pathogenic variants).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with NTHL1 tumor syndrome in order to identify as early as possible sibs with biallelic NTHL1 pathogenic variants who would benefit from appropriate surveillance (beginning at age 18 years), early diagnosis, and treatment of NTHL1-associated tumors.

In general, molecular genetic testing for NTHL1 tumor syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with biallelic NTHL1 pathogenic variants, screening should begin by age 18 years. A history of early cancers in the family may warrant testing prior to age 18 [NCCN 2024].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

NTHL1 tumor syndrome is inherited in an autosomal recessive manner.

Parents of a proband

Sibs of a proband

Offspring of a proband

  • Unless an affected individual's reproductive partner also has NTHL1 tumor syndrome or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in NTHL1.
  • Given the very low carrier frequency of NTHL1 pathogenic variants (see Prevalence), it is unlikely that the reproductive partner of the proband is a carrier of an NTHL1 pathogenic variant unless consanguinity is a factor.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a NTHL1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the NTHL1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Predictive testing for at-risk asymptomatic sibs requires prior identification of the germline NTHL1 pathogenic variants in the family.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – Health Professional Version (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of individuals known to have NTHL1 pathogenic variant(s), particularly if consanguinity is likely and/or if both partners are of the same ancestry.

Prenatal Testing and Preimplantation Genetic Testing

Once the NTHL1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

NTHL1 Tumor Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
NTHL1 16p13​.3 Endonuclease III-like protein 1 NTHL1 NTHL1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for NTHL1 Tumor Syndrome (View All in OMIM)

602656ENDONUCLEASE III-LIKE 1; NTHL1
616415FAMILIAL ADENOMATOUS POLYPOSIS 3; FAP3

Molecular Pathogenesis

The protein encoded by NTHL1, endonuclease III-like protein 1 (NTHL1), is a DNA glycosylase of the base excision repair pathway that removes endogenously damaged nucleotides in DNA [Robertson et al 2009]. Various DNA glycosylases target different types of damage caused by oxidation, deamination, or alkylation. NTHL1 specifically targets oxidized pyrimidine residues in DNA and has apurinic/apyrimidinic lyase activity [Wallace et al 2012]. Subsequently, the repair process completes with the incorporation of the correct nucleotide or elongation of multiple nucleotides by a DNA polymerase and sealing of the remaining nick by a DNA ligase [Svilar et al 2011, Wallace et al 2012, Krokan et al 2014].

To date, all identified NTHL1 pathogenic variants are stop-gain, frameshift, or splice site variants, likely resulting in loss of function of both alleles. Therefore, in affected individuals every cell is NTHL1 deficient, resulting in slow but progressive accumulation of somatic pathogenic variants, thereby increasing the risk of cancer in tissues that are most vulnerable to this type of damage.

Individuals with loss of NTHL1 function develop tumors that have somatic pathogenic variants strongly biased toward C>T transitions, predominantly at non-CpG sites [Weren et al 2015]. Analysis of the somatic mutational patterns in NTHL1-deficient colon organoid clones and in multiple tumors of persons with biallelic germline NTHL1 pathogenic variants revealed that loss of NTHL1 function elicits a specific mutational signature [Drost et al 2017, Grolleman et al 2019]. The resulting mutational process is most prominent in tissues with higher proliferation rates and/or higher rates of oxidative damage and increases the chance that cancer-driver genes are hit by a pathogenic variant. Establishing the mutational pattern in tumor tissue can be of help in proving the pathogenicity of (novel) NTHL1 variants [Pinto et al 2023]. Performing mutational signature analysis can assist in determining if NTHL1 deficiency was the main mutational driver in colorectal adenomas or colorectal cancer [Terlouw et al 2024, Walker et al 2025].

Mechanism of disease causation. Loss of function

Table 6.

NTHL1 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_002528​.6
NP​_002519
c.268C>Tp.Gln90TerFounder/recurrent pathogenic variant 1 [Weren et al 2018, Grolleman et al 2019]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

This variant is common in the Dutch population but has also been observed in affected individuals from different ethnic groups, suggesting that there may be multiple independent founders. Fifteen reported families have been homozygous for this variant [Chubb et al 2016, Belhadj et al 2017, Fostira et al 2018, Altaraihi et al 2019, Grolleman et al 2019, Groves et al 2019].

Chapter Notes

Author Notes

The authors are actively involved in clinical research regarding individuals with NTHL1 tumor syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of NTHL1 tumor syndrome or other considerations.

Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC)
cgaigc.com

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
insight-group.org

Revision History

  • 20 March 2025 (sw) Comprehensive updated posted live
  • 2 April 2020 (sw) Review posted live
  • 17 June 2019 (nh/rk) Original submission

References

Literature Cited

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