Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30753826)
ClinVar Genomic variation as it relates to human health
NM_002528.7(NTHL1):c.211dup (p.Ala71fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002528.7(NTHL1):c.211dup (p.Ala71fs)
Variation ID: 545885 Accession: VCV000545885.25
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2046270-2046271 (GRCh38) [ NCBI UCSC ] 16: 2096271-2096272 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 9, 2018 Oct 20, 2024 Feb 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002528.7:c.211dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002519.2:p.Ala71fs frameshift NM_002528.7:c.211dupG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001318193.2:c.211dup NP_001305122.2:p.Ala71fs frameshift NM_001318194.2:c.24+5dup intron variant NM_002528.5:c.235dupG NC_000016.10:g.2046275dup NC_000016.9:g.2096276dup NG_005895.1:g.1970dup NG_008412.1:g.6596dup LRG_1366:g.6596dup LRG_1366t1:c.211dup LRG_1366p1:p.Ala71fs LRG_487:g.1970dup - Protein change
- A71fs
- Other names
- -
- Canonical SPDI
- NC_000016.10:2046270:CCCCC:CCCCCC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NTHL1 | - | - |
GRCh38 GRCh37 |
1521 | 1642 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000657485.19 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2023 | RCV001310141.3 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 11, 2023 | RCV002256456.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 3
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499695.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Likely pathogenic
(Dec 15, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002528934.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NTHL1 c.235dupG (p.A79GfsX2) variant has been reported in 1 individual with colorectal cancer (PMID 30753826). This variant causes a frameshift at amino acid 79 … (more)
The NTHL1 c.235dupG (p.A79GfsX2) variant has been reported in 1 individual with colorectal cancer (PMID 30753826). This variant causes a frameshift at amino acid 79 that results in premature termination 2 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss-of-function variants in NTHL1 are known to be pathogenic (PMID: 25938944, 26559593). This variant was observed in 1/113298 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 545885). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Oct 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000779220.3
First in ClinVar: Jul 09, 2018 Last updated: Nov 25, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30753826) (less)
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Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004188353.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
|
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Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004192147.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
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Pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242666.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001390595.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala79Glyfs*2) in the NTHL1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ala79Glyfs*2) 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 (rs745671590, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 545885). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002735738.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004041955.11
First in ClinVar: Oct 14, 2023 Last updated: Oct 20, 2024 |
Comment:
NTHL1: PVS1, PM2, PM3
Number of individuals with the variant: 1
|
Comment:
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Ala79Glyfs*2) 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 (rs745671590, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 545885). For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
Comment:
NTHL1: PVS1, PM2, PM3
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30753826)
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Ala79Glyfs*2) 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 (rs745671590, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 545885). For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
Comment:
NTHL1: PVS1, PM2, PM3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. | Grolleman JE | Cancer cell | 2019 | PMID: 30753826 |
| Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors. | Rivera B | The New England journal of medicine | 2015 | PMID: 26559593 |
| A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. | Weren RD | Nature genetics | 2015 | PMID: 25938944 |
Text-mined citations for rs745671590 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.