NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter) AND Hereditary cancer-predisposing syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 18, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000850062.11

Allele description

NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter)

Gene:

NTHL1:nth like DNA glycosylase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter)

Other names:

Q90*; p.Gln82*

HGVS:

NC_000016.10:g.2046238G>A
NG_005895.1:g.1933G>A
NG_008412.1:g.6629C>T
NM_001318193.2:c.244C>T
NM_001318194.2:c.24+42C>T
NM_002528.7:c.244C>TMANE SELECT
NP_001305122.2:p.Gln82Ter
NP_002519.2:p.Gln82Ter
LRG_1366t1:c.244C>T
LRG_1366:g.6629C>T
LRG_1366p1:p.Gln82Ter
LRG_487:g.1933G>A
NC_000016.9:g.2096239G>A
NM_002528.5:c.268C>T
NM_002528.6:c.268C>T

Protein change:

Q82*; GLN90TER

Links:

OMIM: 602656.0001; dbSNP: rs150766139

NCBI 1000 Genomes Browser:

rs150766139

Molecular consequence:

NM_001318194.2:c.24+42C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001318193.2:c.244C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002528.7:c.244C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992218	Academic Department of Medical Genetics, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 26, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001177246	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Oct 18, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18515411, 25938944, 26431160, 26649986, 27713038, 27720914 Citation Link,
SCV002528946	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Feb 18, 2022)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 25938944, 30248171, 30753826 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000992218

Academic Department of Medical Genetics, University of Cambridge

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 26, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV001177246

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Oct 18, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002528946

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Feb 18, 2022)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	3	not provided	research
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3.

Dallosso AR, Dolwani S, Jones N, Jones S, Colley J, Maynard J, Idziaszczyk S, Humphreys V, Arnold J, Donaldson A, Eccles D, Ellis A, Evans DG, Frayling IM, Hes FJ, Houlston RS, Maher ER, Nielsen M, Parry S, Tyler E, Moskvina V, Cheadle JP, et al.

Gut. 2008 Sep;57(9):1252-5. doi: 10.1136/gut.2007.145748. Epub 2008 May 30.

PubMed [citation]

PMID:: 18515411

See all PubMed Citations (9)

Details of each submission

From Academic Department of Medical Genetics, University of Cambridge, SCV000992218.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)
2	not provided	1	not provided	not provided	research	PubMed (1)
3	not provided	1	not provided	not provided	research	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV001177246.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Sema4, Sema4, SCV002528946.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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