ClinVar Genomic variation as it relates to human health
NM_002528.7(NTHL1):c.274C>T (p.Arg92Cys)
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.
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.
Uncertain significance(8); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002528.7(NTHL1):c.274C>T (p.Arg92Cys)
Variation ID: 499145 Accession: VCV000499145.51
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2046208 (GRCh38) [ NCBI UCSC ] 16: 2096209 (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 Apr 2, 2018 May 1, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002528.7:c.274C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002519.2:p.Arg92Cys missense NM_001318193.2:c.274C>T NP_001305122.2:p.Arg92Cys missense NM_001318194.2:c.24+72C>T intron variant NC_000016.10:g.2046208G>A NC_000016.9:g.2096209G>A NG_005895.1:g.1903G>A NG_008412.1:g.6659C>T LRG_1366:g.6659C>T LRG_1366t1:c.274C>T LRG_1366p1:p.Arg92Cys LRG_487:g.1903G>A - Protein change
- R92C
- Other names
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- Canonical SPDI
- NC_000016.10:2046207:G:A
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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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00086
Trans-Omics for Precision Medicine (TOPMed) 0.00087
Exome Aggregation Consortium (ExAC) 0.00089
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
The Genome Aggregation Database (gnomAD), exomes 0.00092
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 | ||
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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. |
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NTHL1 | - | - |
GRCh38 GRCh37 |
1493 | 1599 |
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. |
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Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000592496.37 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 30, 2021 | RCV001017807.9 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2021 | RCV000765258.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV001800825.11 | |
Likely benign (1) |
criteria provided, single submitter
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May 4, 2023 | RCV003945401.1 |
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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Uncertain significance
(Dec 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000704487.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896511.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518403.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Uncertain significance
(Dec 30, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002528953.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NTHL1 c.298C>T (p.R100C) variant has been reported in individuals with breast cancer, ovarian cancer, precursor B-cell lymphoblastic leukemia as well as in controls (PMID: … (more)
The NTHL1 c.298C>T (p.R100C) variant has been reported in individuals with breast cancer, ovarian cancer, precursor B-cell lymphoblastic leukemia as well as in controls (PMID: 33332384, 30584090, 33980861). It was observed in 32/10344 chromosomes of the Ashkenazi Jewish subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 499145). In silico tools suggest the impact of the variant on protein function is deleterious though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Nov 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579693.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PP3, BP1
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Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002526088.2
First in ClinVar: Jun 16, 2022 Last updated: Dec 24, 2022 |
Comment:
The NTHL1 c.298C>T (p.Arg100Cys) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2096209-G-A). Six of seven in silico tools predict a … (more)
The NTHL1 c.298C>T (p.Arg100Cys) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2096209-G-A). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported as individuals with colorectal cancer, breast cancer and precursor B-cell acute lymphoblastic leukemia (PMID: 32620917, 32295625, 32620917). It has also been identified in 3/1358 non-cancer controls collected as part of a study of individuals with multiple primary cancers (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with familial adenomatous polyposis. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. (less)
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Uncertain significance
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001826661.6
First in ClinVar: Sep 08, 2021 Last updated: Jul 29, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian cancer, breast cancer, and leukemia … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian cancer, breast cancer, and leukemia (Li et al., 2019; Byrjalsen et al., 2020; Li et al., 2021); This variant is associated with the following publications: (PMID: 30584090, 29641532, 33980861, 33332384, 20054297, 32906206) (less)
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Likely benign
(Aug 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047233.3
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
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Uncertain significance
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551608.5
First in ClinVar: Jul 27, 2022 Last updated: Feb 14, 2024 |
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001042052.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Likely benign
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585530.9
First in ClinVar: Oct 22, 2022 Last updated: Apr 15, 2024 |
Comment:
NTHL1: BP1
Number of individuals with the variant: 1
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Likely benign
(Jun 14, 2021)
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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
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Ambry Genetics
Accession: SCV001178957.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(May 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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NTHL1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004769780.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919486.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953865.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974929.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. | Li N | NPJ breast cancer | 2021 | PMID: 33980861 |
Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes. | Byrjalsen A | PLoS genetics | 2020 | PMID: 33332384 |
Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India. | Narang A | Human mutation | 2020 | PMID: 32906206 |
Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. | Li C | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 30584090 |
Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. | Dalgliesh GL | Nature | 2010 | PMID: 20054297 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NTHL1 | - | - | - | - |
Text-mined citations for rs148104494 ...
HelpRecord last updated May 08, 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.