rs150766139

Positions:

• chr16-2046238-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002528.7(NTHL1):​c.244C>T​(p.Gln82Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,613,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: NTHL1 NM_002528.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 U:1 O:1
• Conservation: PhyloP100: 0.670

Genes affected

NTHL1 (HGNC:8028): (nth like DNA glycosylase 1) The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2046238-G-A is Pathogenic according to our data. Variant chr16-2046238-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2046238-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTHL1	NM_002528.7	c.244C>T	p.Gln82Ter	stop_gained	2/6	ENST00000651570.2	NP_002519.2
NTHL1	NM_001318193.2	c.244C>T	p.Gln82Ter	stop_gained	2/5		NP_001305122.2
NTHL1	XM_047434171.1	c.-36C>T		5_prime_UTR_variant	2/6		XP_047290127.1
NTHL1	NM_001318194.2	c.24+42C>T		intron_variant			NP_001305123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTHL1	ENST00000651570.2	c.244C>T	p.Gln82Ter	stop_gained	2/6		NM_002528.7	ENSP00000498421

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00141 AC: 354 AN: 250862 Hom.: 0 AF XY: 0.00143 AC XY: 194 AN XY: 135816

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00162 AC: 2364 AN: 1460944 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 1172 AN XY: 726740

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00476

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74432

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00149 Hom.: 1

Bravo AF: 0.000986

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00153 AC: 186

EpiCase AF: 0.00224

EpiControl AF: 0.00190

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 3 Pathogenic:14 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 6/19/2020 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Oct 02, 2023	ACMG criteria used to clasify this variant: PVS1, PS4, PM3_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 03, 2023	The NTHL1 c.244C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM3_Strong) The NTHL1 c.244C>T variant is a single nucleotide change which is predicted to result in the premature termination of the protein product at codon 82 (PVS1). The variant has been widely reported in the literature in affected patients (PMID:18515411, 25938944, 26431160, 26559593, 27720914, 31285513) (PS4_Moderate). It has been detected as homozygous in 4 unrelated patients and as compound het with another path/likely path variant in 3 patients (eg. PMID:33454955) (PM3_strong). The variant has been reported in dbSNP (rs150766139), in population databases (gnomAD 204/152138 alleles, 0 hom) and as disease causing in the HGMD database (CM088021). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 192319). Unaffected heterozygous carriers of this variant have been reported (PMID:18515411, PMID:25938944, PMID:31285513). Note: this variant is also known as (NM_002528.6):c.268C>T; p.Gln90*. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 02, 2022	ACMG classification criteria: PVS1 very strong, PM3 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 01, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	This pathogenic variant is denoted NTHL1 c.268C>T at the cDNA level and p.Gln90Ter (Q90X) (aka: NM_001318193.2:c.244C>T; NP_001305122.2:p.Gln82Ter) at the protein level. The substitution creates a nonsense variant, which changes a Glycine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in several individuals with colorectal cancer and/or adenomas (Dallosso 2008, Rivera 2015, Timofeeva 2015, Weren 2015). Weren et al. (2015) identified NTHL1 Gln90Ter in the homozygous state in 7 individuals from three families with a history of multiple colorectal adenomas and/or colorectal cancer. Additionally, Rivera et al. (2015) identified NTHL1 Gln90Ter in the compound heterozygous state with a canonical splice variant, confirmed to be in trans through familial testing, in an individual with colon cancer, multiple colorectal adenomas, and other neoplasms. Lastly, other studies identified NTHL1 Gln90Ter in the homozygous or compound heterozygous state in several unrelated individuals with colorectal adenomas and colorectal cancer (Chubb 2016, Belhadj 2017, Broderick 2017). Based on currently available information, we consider NTHL1 Gln90Ter to be pathogenic. Of note, NTHL1-Associated Polyposis (NAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in NTHL1. Although this variant is considered pathogenic, a second pathogenic variant, as would be required for expression of the recessive condition NAP, was not detected in this individual. We cannot exclude the possibility that this patient harbors a second disease-causing NTHL1 pathogenic variant that is undetectable by this test. NTHL1 has only recently been described in association with cancer predisposition and the risks are not well understood. Based on available data, the presence of two pathogenic variants in NTHL1 is indicative of NTHL1-Associated Polyposis (NAP), an autosomal recessive condition that may confer an increased risk for colorectal cancer and polyps. Although the development of colorectal cancer and attenuated polyposis appears to be the predominant feature of NAP, multiple case reports have described individuals with NAP to have developed multiple extracolonic neoplasms, including breast, endometrial, bladder, and skin cancers as well as several benign findings (Rivera 2015, Weren 2015, Belhadj 2017). The National Comprehensive Cancer Network has management guidelines for individuals with two pathogenic variants in NTHL1 (NCCN) (ClinVar- GeneDx; modified) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 18, 2022	The NTHL1 c.268C>T (p.Gln90Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been reported as homozygous in individuals across multiple families with colon cancer and/or adenomatous polyposis (PMID: 25938944, 27720914, 30248171, 31645984). It has also been reported as compound heterozygous in an individual with adenocarcinoma of the colon and >30 colorectal adenomas (PMID: 26559593). This variant has a maximum subpopulation frequency of 0.35% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). It is referred to as p.Gln82Ter in the NM_002528 transcript. In summary, this variant meets criteria to be classified as pathogenic. -

not provided Pathogenic:12 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NTHL1: PVS1, PP1:Strong -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jun 08, 2021	PP5, PP1, BS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2023	PP1, PP4, PM3, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27712984, 29105096, 31645984, 18515411, 23852950, 26553438, 25525159, 26427841, 25938944, 26559593, 27713038, 27329137, 28306719, 26431160, 27720914, 29454559, 29909963, 30552997, 29900613, 30753826, 31227763, 31243857, 31285513, 30859360, 30248171, 30267214, 30877237, 31263571, 31980526, 32581362, 33193653, 32860789, 32949222) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Gln90*) in the NTHL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NTHL1 are known to be pathogenic (PMID: 25938944, 26559593). This variant is present in population databases (rs150766139, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with multiple adenomatous polyps and colorectal cancer (PMID: 25938944, 26559593, 27720914). 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: 192319). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2021	This variant causes the premature termination of NTHL1 protein synthesis. In the published literature, this variant has been reported in numerous compound heterozygous and homozygous individuals affected with colorectal cancer, colorectal adenomas, and other neoplasms in the published literature (PMID: 33193653 (2020), 30753826 (2019), 27720914 (2017), 27713038 (2017), 26559593 (2015), 26553438 (2015), 25938944 (2015), 18515411 (2008)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2021	The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 2 of the NTHL1 gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with polyposis and/or colorectal cancer (Dallosso AR et al. Gut 2008 Sep;57:1252-5; Weren RD et al. Nat. Genet. 2015 Jun;47:668-71; Kuiper RP et al. Oncotarget 2015 Oct;6:34069-70; Timofeeva MN et al. Sci Rep. 2015 Nov 10;5:16286; Rivera et al. N. Engl. J. Med. 2015 Dec;373:e33; Broderick P et al. Gastroenterology 2017 Jan;152:75-77.e4; Belhadj S et al. Clin. Gastroenterol. Hepatol. 2017 Mar;15:461-462; Whitworth J et al. Am J Hum Genet. 2018 Jul 5;103(1):3-18; Fostira F et al. Clin Genet. 2018 Sep 24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

NTHL1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

The NTHL1 c.268C>T variant is predicted to result in premature protein termination (p.Gln90*). This variant has been reported in the homozygous or compound heterozygous state in individuals with multiple colorectal adenomas and an increased susceptibility to colorectal, endometrial, skin, breast and bladder cancer (Rivera et al. 2015. PubMed ID: 26559593; Weren et al. 2015. PubMed ID: 25938944; Belhadj et al. 2017. PubMed ID: 27720914). This variant was found in the homozygous state in seven individuals from three families that had a history of colorectal adenomas and/or colorectal cancer (Weren et al. 2015. PubMed ID: 25938944). Of note, the three affected women in this study all developed endometrial cancer. Functional studies in B-lymphocytes from homozygous carriers indicate that this variant results in nonsense mediated decay and a ten-fold reduction in NTHL1 RNA expression in comparison to controls (Weren et al. 2015. PubMed ID: 25938944). This variant is reported in 0.35% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/192319/). Nonsense variants in NTHL1 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive NTHL1-related cancer predisposition. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A
Vest4		0.40
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150766139; hg19: chr16-2096239;