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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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002528934Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)
Likely pathogenic
(Dec 15, 2021)
germlinecuration

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

Citation Link,

SCV002735738Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Aug 11, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV002735738.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024