Submissions for variant NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr)

gnomAD frequency: 0.00155  dbSNP: rs1805378

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000896408	SCV001040497	likely benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001023853	SCV001185786	likely benign	Hereditary cancer-predisposing syndrome	2020-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000767388	SCV001737453	likely benign	Familial adenomatous polyposis 3	2021-10-28	criteria provided, single submitter	clinical testing	The NTHL1 c.527T>C (p.Ile176Thr) missense change has a maximum non-founder subpopulation frequency of 0.3% and a maximum founder subpopulation frequency of 0.54% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2094653-A-G?dataset=gnomad_r2_1). This is higher than expected for a pathogenic variant in NTHL1 (BS1; PMID: 33454955). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported as heterozygous in individuals with colorectal cancer and adenomatous polyposis (PMID: 31227763, 31285513). It has also been reported as homozygous or compound heterozygous in three individuals with cancer, one of whom has a history of >50 adenomas (PMID: 33454955). This variant has also been reported as homozygous 1x in the gnomAD v2.1.1 database. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, PP3.
GeneDx	RCV000896408	SCV001875286	uncertain significance	not provided	2022-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21167187, 15159313, 33454955, 17029639, 23852950, 16741161, 29641532, 31227763, 31243857, 31285513, 32295625, 33980861)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000896408	SCV002010424	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000896408	SCV002047110	likely benign	not provided	2023-09-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767388	SCV002049964	uncertain significance	Familial adenomatous polyposis 3	2021-07-05	criteria provided, single submitter	clinical testing	The NTHL1 c.503T>C; p.Ile168Thr variant (rs1805378), also known in alternative nomenclature as p.Ile176Thr, is reported in the literature in multiple heterozygous individuals affected with colorectal cancer or attenuated adenomatous polyposis, although none of these individuals carried a second reported NTHL1 variant (Belhadj 2019, Lorca 2019). This variant is found in the general population with an overall allele frequency of 0.18% (500/277380 alleles, including one homozygote) in the Genome Aggregation Database. The isoleucine at codon 168 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.876). However, due to limited information, the clinical significance of the p.Ile168Thr variant is uncertain at this time. References: Belhadj et al. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. Sci Rep. 2019 Jun 21;9(1):9020. PMID: 31227763. Lorca et al. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing. Sci Rep. 2019 Jul 8;9(1):9814.
Genetic Services Laboratory, University of Chicago	RCV001816746	SCV002066415	likely benign	not specified	2021-07-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001023853	SCV002528982	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001816746	SCV002551598	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000896408	SCV002563279	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	NTHL1: BS1
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000767388	SCV000844933	uncertain significance	Familial adenomatous polyposis 3	2018-06-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000896408	SCV001550289	likely benign	not provided		no assertion criteria provided	clinical testing	The NTHL1 p.I58T variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs1805378) and in ClinVar (classified as uncertain significance by Molecular Oncology Laboratory, Hospital Clínico San Carlos for Familial adenomatous polyposis 3). The variant was also identified in control databases in 500 of 277380 chromosomes (1 homozygous) at a frequency of 0.001803 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 56 of 10282 chromosomes (freq: 0.005446), Latino in 107 of 35394 chromosomes (freq: 0.003023), Other in 17 of 7160 chromosomes (freq: 0.002374), European (non-Finnish) in 279 of 127442 chromosomes (freq: 0.002189), South Asian in 23 of 30596 chromosomes (freq: 0.000752), European (Finnish) in 9 of 21854 chromosomes (freq: 0.000412), African in 7 of 24764 chromosomes (freq: 0.000283), and East Asian in 2 of 19888 chromosomes (freq: 0.000101). The p.Ile58 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003953261	SCV004769732	likely benign	NTHL1-related disorder	2022-03-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).