NM_002528.7(NTHL1):c.709dup (p.Ile237fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 2, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002386918.2

Allele description [Variation Report for NM_002528.7(NTHL1):c.709dup (p.Ile237fs)]

NM_002528.7(NTHL1):c.709dup (p.Ile237fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_002528.7(NTHL1):c.709dup (p.Ile237fs)

HGVS:

NC_000016.10:g.2040216dup
NG_008412.1:g.12652dup
NG_047104.1:g.18349dup
NM_001318193.2:c.538dup
NM_001318194.2:c.379dup
NM_002528.5:c.733dup
NM_002528.7:c.709dupMANE SELECT
NP_001305122.2:p.Ile180fs
NP_001305123.1:p.Ile127fs
NP_002519.2:p.Ile237fs
LRG_1366t1:c.709dup
LRG_1366:g.12652dup
LRG_1366p1:p.Ile237fs
NC_000016.9:g.2090215_2090216insT
NC_000016.9:g.2090217dup
NM_002528.5:c.733dupA
NM_002528.6:c.733dup
NM_002528.7:c.709dup

Protein change:

I127fs

Links:

dbSNP: rs2150938411

NCBI 1000 Genomes Browser:

rs2150938411

Molecular consequence:

NM_001318193.2:c.538dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318194.2:c.379dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002528.7:c.709dup - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002674942	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002674942

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 2, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.

Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, Ligtenberg MJL, Vos JR, Ten Broeke SW, de Miranda NFCC, Kuiper RA, Kamping EJ, Jansen EAM, Vink-Börger ME, Popp I, Lang A, Spier I, Hüneburg R, James PA, Li N, Staninova M, Lindsay H, et al.

Cancer Cell. 2019 Feb 11;35(2):256-266.e5. doi: 10.1016/j.ccell.2018.12.011.

PubMed [citation]

PMID:: 30753826

Details of each submission

From Ambry Genetics, SCV002674942.2

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

Description

The c.733dupA variant, located in coding exon 5 of the NTHL1 gene, results from a duplication of A at nucleotide position 733, causing a translational frameshift with a predicted alternate stop codon (p.I245Nfs*28). This variant has been identified in conjunction with a second truncating allele in an individual with an adenomatous polyp and CRC (Grolleman JE et al. Cancer Cell, 2019 02;35:256-266.e5). This alteration occurs at the 3' terminus of theNTHL1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 68 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 majority of available evidence to date, this variant is likely to be pathogenic.

#	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: Jun 17, 2024

ClinVar

Relating variation to medicine