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

gnomAD frequency: 0.00026  dbSNP: rs146347092

Total submissions: 10

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	2024-03-24	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.