NTHL1 plays a role in base-excision repair pathway and was first reported in relation to autosomal recessive NTHL1-deficiency tumor predisposition syndrome in 2015 (Weren et al., PMID: 25938944). The condition is primarily characterized by adenomatous polyposis of colon (~10-50), colorectal cancer, and breast cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found NTHL1-deficiency tumor predisposition syndrome (MONDO:0100502) is the only one disease entity associated with this gene. About 30 individuals carrying biallelic loss-of-function variants, most commonly NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter) (formerly referred to as p.Gln90Ter) in line with its relatively high minor allele frequency (~0.1%) in the population databases, have been reported to date and 5 of them along with their affected siblings are included in this curation (PMIDs: 25938944, 30753826, 27720914, 26559593). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity has been demonstrated to be loss-of-function resulting in deficient NTHL1 activity (PMID: 25938944). A specific mutational signature due to a high percentage of somatic C>T transitions (COSMIS Signature 30) in cancer driver genes such as KRAS, APC, TP53, PIK3CA has been identified on tested tumor samples, and the preliminary data also suggest other primary tumors, i.e. urothelial carcinoma of the bladder, might also be linked to NTHL1 deficiency per mutational profiling of such tumors (PMID: 30753826). This gene-disease relationship is also supported by experimental evidence (3.85 points from human cell models, in vitro functional assays, animal models, etc.) (PMIDs: 8990169, 19346169, 30552997, 28912133). Particularly, human colonic stem cells-derived organoids devoid of NTHL1 activity phenocopied the somatic mutational signature detected in tumoral samples of individuals carrying biallelic loss-of-function NTHL1 variants. In summary, NTHL1 is definitively associated with autosomal recessive NTHL1-deficiency tumor predisposition syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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