ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.835C>T (p.Gln279Ter)

gnomAD frequency: 0.00026  dbSNP: rs146347092
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760534 SCV000890425 likely pathogenic not provided 2023-05-30 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 27 amino acids are lost, disrupting residues within the critical iron-sulfur motifs (Aspinwall et al., 1997; Hilbert et al., 1997; Ikeda et al., 1998); Published functional studies demonstrate defective base excision repair (Shinmura et al., 2018); Observed with a second NTHL1 variant in unrelated patients with NTHL1-associated polyposis-related neoplasms in published literature, however it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Chubb et al., 2016, Broderick et al., 2017, Grolleman et al., 2019); Observed in the heterozygous state in individuals with breast cancer and colorectal cancer in published literature (Drost et al., 2017; Bertelsen et al., 2019; Elsayed et al., 2020; Li et al., 2021); This variant is associated with the following publications: (PMID: 30753826, 30859360, 27713038, 27329137, 29641532, 31243857, 30877237, 29105096, 28912133, 32860789, 33980861, 31263571, 26553438, Gomez2021[article], 30552997, 8990169, 9045706, 9705289, 33087284)
Invitae RCV000760534 SCV000958633 pathogenic not provided 2024-01-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln287*) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the NTHL1 protein. This variant is present in population databases (rs146347092, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with polyposis, colorectal cancer and breast cancer (PMID: 27329137, 28912133, 30753826; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 620182). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NTHL1 function (PMID: 30552997). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001018044 SCV001179222 pathogenic Hereditary cancer-predisposing syndrome 2021-08-11 criteria provided, single submitter clinical testing The p.Q287* pathogenic mutation (also known as c.859C>T), located in coding exon 6 of the NTHL1 gene, results from a C to T substitution at nucleotide position 859. This changes the amino acid from a glutamine to a stop codon within coding exon 6. In two studies, this alteration was reported in conjunction with the same NTHL1 pathogenic variant in an individual with early-onset rectal cancer and in an individual with polyposis; however, the phase (whether in cis or trans) was not determined in either case (Chubb D et al. Nat Commun, 2016 06;7:11883; Broderick P et al. Gastroenterology, 2017 01;152:75-77.e4). This alteration was also reported as a germline variant in a breast cancer patient whose tumor showed loss of heterozygosity (Drost J et al. Science, 2017 10;358:234-238). In addition, this variant has been identified in trans with a pathogenic NTHL1 variant or in the homozygous state in probands with polyposis and/or colorectal cancer ((Grolleman JE et al. Cancer Cell, 2019 02;35:256-266.e5; Ambry internal data, personal communication with external laboratory). Recently, this alteration was shown to have reduced DNA glycosylase activity compared to wild-type NTHL1 in an in vitro functional study (Shinmura K et al. Free Radic. Biol. Med., 2019 02;131:264-273). This alteration occurs at the 3' terminus of theNTHL1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 26 amino acids of the protein. However, based on internal structural analysis, this truncation disrupts the endonuclease III domain of NTHL1, including an iron-sulfur cluster binding region important to proper function (Fromme JC et al. EMBO J, 2003 Jul;22:3461-71; Barton JK et al. Annu Rev Biochem, 2019 06;88:163-190; Das L et al. DNA Repair (Amst), 2020 09;93:102920). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Sema4, Sema4 RCV001018044 SCV002529027 likely pathogenic Hereditary cancer-predisposing syndrome 2022-01-19 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000760534 SCV002551591 pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV001535451 SCV002761393 likely pathogenic Familial adenomatous polyposis 3 2022-01-05 criteria provided, single submitter clinical testing The heterozygous variant c.859C>T was detected in exon 6 (last exon) of the NTHL1 gene. This variant results in a premature stop codon, p.(Gln287*), which is predicted to disrupt the last 26 amino acid resides of the NTHL1 protein. This variant is recorded in ClinVar as likely pathogenic (twice) and uncertain significance (once). This variant was reported to co-occur with other truncating NTHL1 variants (p.(Gln90*) phase unknown and p.(Trp269*) in trans) in individuals with colorectal cancer and multiple adenomatous polyps, respectively (Chubb et al, Nat Commun (2016) 7:11883 and Grolleman et al, Cancer Cell (2019) 35(2):256-266.e5). In an individual with breast cancer who carries this variant, the tumour showed loss of heterozygosity (Drost et al, Science (2017) 358(6360):234-238). Functional studies show that this variant leads to reduced DNA glycosylase activity compared to wild-type protein (Shinmura et al, Free Radic Biol Med (2019) 131:264-273). This variant is observed at allele frequencies up to 0.053% in population databases (ESP and gnomAD). Based on current knowledge, this is considered a pathogenic (Class 5) variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760534 SCV002774284 likely pathogenic not provided 2021-07-14 criteria provided, single submitter clinical testing A functional study indicated that this variant significantly reduced the DNA glycosylase activity of the NTHL1 protein in vitro (PMID: 30552997 (2019)). In addition, this variant has been reported in combination with a second deleterious NTHL1 variant in individuals with colorectal cancer and polyps (PMIDs: 30753826 (2019) and 27329137 (2016)). In the heterozygous state this variant has been reported in individuals with breast, ovarian, and colorectal cancer, as well as in controls (PMIDs: 33980861 (2021), 32860789 (2020), 29641532 (2018), and 28912133 (2017)). Based on the available information, this variant is classified as likely pathogenic.
Myriad Genetics, Inc. RCV001535451 SCV004188349 pathogenic Familial adenomatous polyposis 3 2023-09-05 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics RCV001535451 SCV004192081 likely pathogenic Familial adenomatous polyposis 3 2023-10-23 criteria provided, single submitter clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535451 SCV001749364 not provided Familial adenomatous polyposis 3 no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 06-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.