Frameshift variant predicted to result in protein truncation, as the last 68 amino acids are replaced with 27 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; 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.709dup (p.Ile237fs)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002528.7(NTHL1):c.709dup (p.Ile237fs)
Variation ID: 1515221 Accession: VCV001515221.12
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2040214-2040215 (GRCh38) [ NCBI UCSC ] 16: 2090215-2090216 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 28, 2022 Jun 17, 2024 Dec 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002528.7:c.709dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002519.2:p.Ile237fs frameshift NM_001318193.2:c.538dup NP_001305122.2:p.Ile180fs frameshift NM_001318194.2:c.379dup NP_001305123.1:p.Ile127fs frameshift NM_002528.5:c.733dup NM_002528.5:c.733dupA NM_002528.6:c.733dup NC_000016.10:g.2040216dup NC_000016.9:g.2090217dup NG_008412.1:g.12652dup NG_047104.1:g.18349dup LRG_1366:g.12652dup LRG_1366t1:c.709dup LRG_1366p1:p.Ile237fs - Protein change
- I237fs, I127fs, I180fs
- Other names
- -
- Canonical SPDI
- NC_000016.10:2040214:TT:TTT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
1522 | 1643 | |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 14, 2023 | RCV002020931.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 2, 2023 | RCV002386918.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 28, 2023 | RCV003458240.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003842331.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 68 amino acids are replaced with 27 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 68 amino acids are replaced with 27 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; 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 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004188370.1
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.
|
|
|
Likely pathogenic
(Jul 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222222.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant is predicted to create a premature stop codon near the last exon of NTHL1 gene, thus it is not expected to undergo … (more)
This frameshift variant is predicted to create a premature stop codon near the last exon of NTHL1 gene, thus it is not expected to undergo nonsense mediated decay. However, this variant disrupts the evolutionary conserved Endo III domain of NTHL1, which contains functionally important DNA binding domains and DNA glycosylase active sites (PMIDs: 33087284 (2020), 9705289 (1998), 9045706 (1997)). This variant has been reported in an individual with NTHL1 tumor syndrome (PMID: 30753826 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002304847.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile245Asnfs*28) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ile245Asnfs*28) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acid(s) of the NTHL1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of NTHL1-related conditions (PMID: 30753826). ClinVar contains an entry for this variant (Variation ID: 1515221). This variant disrupts a region of the NTHL1 protein in which other variant(s) (p.Gln287*) have been determined to be pathogenic (PMID: 27329137, 28912133, 30753826; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Nov 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002674942.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004192190.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This frameshift variant is predicted to create a premature stop codon near the last exon of NTHL1 gene, thus it is not expected to undergo nonsense mediated decay. However, this variant disrupts the evolutionary conserved Endo III domain of NTHL1, which contains functionally important DNA binding domains and DNA glycosylase active sites (PMIDs: 33087284 (2020), 9705289 (1998), 9045706 (1997)). This variant has been reported in an individual with NTHL1 tumor syndrome (PMID: 30753826 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Ile245Asnfs*28) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acid(s) of the NTHL1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of NTHL1-related conditions (PMID: 30753826). ClinVar contains an entry for this variant (Variation ID: 1515221). This variant disrupts a region of the NTHL1 protein in which other variant(s) (p.Gln287*) have been determined to be pathogenic (PMID: 27329137, 28912133, 30753826; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
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, as the last 68 amino acids are replaced with 27 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; 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 frameshift variant is predicted to create a premature stop codon near the last exon of NTHL1 gene, thus it is not expected to undergo nonsense mediated decay. However, this variant disrupts the evolutionary conserved Endo III domain of NTHL1, which contains functionally important DNA binding domains and DNA glycosylase active sites (PMIDs: 33087284 (2020), 9705289 (1998), 9045706 (1997)). This variant has been reported in an individual with NTHL1 tumor syndrome (PMID: 30753826 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Ile245Asnfs*28) in the NTHL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acid(s) of the NTHL1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of NTHL1-related conditions (PMID: 30753826). ClinVar contains an entry for this variant (Variation ID: 1515221). This variant disrupts a region of the NTHL1 protein in which other variant(s) (p.Gln287*) have been determined to be pathogenic (PMID: 27329137, 28912133, 30753826; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
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 |
| Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. | Drost J | Science (New York, N.Y.) | 2017 | PMID: 28912133 |
| Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. | Chubb D | Nature communications | 2016 | PMID: 27329137 |
Text-mined citations for rs2150938411 ...
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 Sep 29, 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.