NM_002528.7(NTHL1):c.211dup (p.Ala71fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 11, 2023
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:: RCV002256456.5

Allele description [Variation Report for NM_002528.7(NTHL1):c.211dup (p.Ala71fs)]

NM_002528.7(NTHL1):c.211dup (p.Ala71fs)

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.211dup (p.Ala71fs)

HGVS:

NC_000016.10:g.2046275dup
NG_005895.1:g.1970dup
NG_008412.1:g.6596dup
NM_001318193.2:c.211dup
NM_001318194.2:c.24+5dup
NM_002528.7:c.211dupMANE SELECT
NP_001305122.2:p.Ala71fs
NP_002519.2:p.Ala71fs
LRG_1366t1:c.211dup
LRG_1366:g.6596dup
LRG_1366p1:p.Ala71fs
LRG_487:g.1970dup
NC_000016.9:g.2096271_2096272insC
NC_000016.9:g.2096276dup
NM_002528.5:c.235dup
NM_002528.5:c.235dupG
NM_002528.6:c.235dup
NM_002528.7:c.211dup
NM_002528.7:c.211dupGMANE SELECT

Protein change:

A71fs

Links:

dbSNP: rs745671590

NCBI 1000 Genomes Browser:

rs745671590

Molecular consequence:

NM_001318193.2:c.211dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002528.7:c.211dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318194.2:c.24+5dup - intron variant - [Sequence Ontology: SO:0001627]

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

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unnamed protein product [Mus musculus]
unnamed protein product [Mus musculus]
gi|74192948|dbj|BAE34977.1|

Protein
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Preface - Systems to Rate the Strength Of Scientific Evidence
MULTISPECIES: DoxX family protein [Enterobacteriaceae]
MULTISPECIES: DoxX family protein [Enterobacteriaceae]
gi|745784091|ref|WP_039077516.1|

Protein
golgin subfamily B member 1 isoform X2 [Homo sapiens]
golgin subfamily B member 1 isoform X2 [Homo sapiens]
gi|2462589193|ref|XP_054202201.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002528934	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Dec 15, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 30753826, 25938944, 26559593 Citation Link,
SCV002735738	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 11, 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

SCV002528934

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Dec 15, 2021)

germline

curation

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

Citation Link,

SCV002735738

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 11, 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, curation

Citations

PubMed

A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer.

Weren RD, Ligtenberg MJ, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, Hoischen A, Shendure J, Boyle EA, Kamping EJ, Nagtegaal ID, Tops BB, Nagengast FM, Geurts van Kessel A, van Krieken JH, Kuiper RP, Hoogerbrugge N.

Nat Genet. 2015 Jun;47(6):668-71. doi: 10.1038/ng.3287. Epub 2015 May 4.

PubMed [citation]

PMID:: 25938944

Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors.

Rivera B, Castellsagué E, Bah I, van Kempen LC, Foulkes WD.

N Engl J Med. 2015 Nov 12;373(20):1985-6. doi: 10.1056/NEJMc1506878. Erratum in: N Engl J Med. 2015 Dec 17;373(25):e33. doi: 10.1056/NEJMx150043.

PubMed [citation]

PMID:: 26559593

See all PubMed Citations (3)

Details of each submission

From Sema4, Sema4, SCV002528934.1

#	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

From Ambry Genetics, SCV002735738.3

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

Description

The c.235dupG pathogenic mutation, located in coding exon 2 of the NTHL1 gene, results from a duplication of G at nucleotide position 235, causing a translational frameshift with a predicted alternate stop codon (p.A79Gfs*2). This mutation has been identified in trans with a second truncating mutation in an individual with mixed polyposis and multiple malignancies (Grolleman JE et al. Cancer Cell, 2019 02;35:256-266.e5). 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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