ClinVar Miner

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

gnomAD frequency: 0.00155  dbSNP: rs1805378
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000896408 SCV001040497 likely benign not provided 2024-02-01 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 2024-02-06 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000896408 SCV002563279 likely benign not provided 2023-10-01 criteria provided, single submitter clinical testing NTHL1: BS1
PreventionGenetics, part of Exact Sciences RCV003953261 SCV004769732 likely benign NTHL1-related disorder 2022-03-11 criteria provided, single submitter 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).
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.

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