ClinVar Genomic variation as it relates to human health
NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr)
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(5); Likely benign(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002528.7(NTHL1):c.503T>C (p.Ile168Thr)
Variation ID: 587357 Accession: VCV000587357.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2044652 (GRCh38) [ NCBI UCSC ] 16: 2094653 (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 21, 2019 May 12, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002528.7:c.503T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002519.2:p.Ile168Thr missense NM_001318193.2:c.355-926T>C intron variant NM_001318194.2:c.173T>C NP_001305123.1:p.Ile58Thr missense NC_000016.10:g.2044652A>G NC_000016.9:g.2094653A>G NG_005895.1:g.347A>G NG_008412.1:g.8215T>C LRG_1366:g.8215T>C LRG_1366t1:c.503T>C LRG_1366p1:p.Ile168Thr LRG_487:g.347A>G - Protein change
- I168T, I58T
- Other names
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- Canonical SPDI
- NC_000016.10:2044651:A:G
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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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0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00125
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00139
The Genome Aggregation Database (gnomAD) 0.00155
Trans-Omics for Precision Medicine (TOPMed) 0.00190
The Genome Aggregation Database (gnomAD), exomes 0.00193
Exome Aggregation Consortium (ExAC) 0.00195
- 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 | ||
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HI score
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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 (3) |
criteria provided, conflicting classifications
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Oct 28, 2021 | RCV000767388.19 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000896408.34 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 22, 2022 | RCV001023853.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV001816746.13 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 11, 2022 | RCV003953261.1 |
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
(Jul 05, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049964.1
First in ClinVar: Jan 05, 2022 Last updated: Jan 05, 2022 |
Comment:
The NTHL1 c.503T>C; p.Ile168Thr variant (rs1805378), also known in alternative nomenclature as p.Ile176Thr, is reported in the literature in multiple heterozygous individuals affected with colorectal … (more)
The NTHL1 c.503T>C; p.Ile168Thr variant (rs1805378), also known in alternative nomenclature as p.Ile176Thr, is reported in the literature in multiple heterozygous individuals affected with colorectal cancer or attenuated adenomatous polyposis, although none of these individuals carried a second reported NTHL1 variant (Belhadj 2019, Lorca 2019). This variant is found in the general population with an overall allele frequency of 0.18% (500/277380 alleles, including one homozygote) in the Genome Aggregation Database. The isoleucine at codon 168 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.876). However, due to limited information, the clinical significance of the p.Ile168Thr variant is uncertain at this time. References: Belhadj et al. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. Sci Rep. 2019 Jun 21;9(1):9020. PMID: 31227763. Lorca et al. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing. Sci Rep. 2019 Jul 8;9(1):9814. (less)
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Likely benign
(Jul 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066415.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Jan 22, 2022)
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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: SCV002528982.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NTHL1 c.527T>C (p.I176T) variant has been reported as heterozygous in at least 6 individuals with attenuated adenomatous polyposis, colorectal cancer and ovarian cancer (PMID: … (more)
The NTHL1 c.527T>C (p.I176T) variant has been reported as heterozygous in at least 6 individuals with attenuated adenomatous polyposis, colorectal cancer and ovarian cancer (PMID: 31285513, 31227763, 32581083). It has also been reported as homozygous in at least 2 individuals with breast, prostate and endometrial cancer (PMID: 33454955). A colorectal and breast cancer study found no significant differences in variant frequency between cases and controls (PMID: 23852950, 33980861). This variant was observed in 56/10282 chromosomes in the Ashkenazi Jewish population, with 1 homozygote, according to the Genome Aggregation Database (PMID: 27535533). 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 variant has been reported in ClinVar (Variation ID 587357). 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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Likely benign
(Oct 28, 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: SCV001737453.4
First in ClinVar: Jun 19, 2021 Last updated: Dec 24, 2022 |
Comment:
The NTHL1 c.527T>C (p.Ile176Thr) missense change has a maximum non-founder subpopulation frequency of 0.3% and a maximum founder subpopulation frequency of 0.54% in gnomAD v2.1.1 … (more)
The NTHL1 c.527T>C (p.Ile176Thr) missense change has a maximum non-founder subpopulation frequency of 0.3% and a maximum founder subpopulation frequency of 0.54% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2094653-A-G?dataset=gnomad_r2_1). This is higher than expected for a pathogenic variant in NTHL1 (BS1; PMID: 33454955). Seven 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 heterozygous in individuals with colorectal cancer and adenomatous polyposis (PMID: 31227763, 31285513). It has also been reported as homozygous or compound heterozygous in three individuals with cancer, one of whom has a history of >50 adenomas (PMID: 33454955). This variant has also been reported as homozygous 1x in the gnomAD v2.1.1 database. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, PP3. (less)
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Uncertain significance
(Apr 04, 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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GeneDx
Accession: SCV001875286.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21167187, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21167187, 15159313, 33454955, 17029639, 23852950, 16741161, 29641532, 31227763, 31243857, 31285513, 32295625, 33980861) (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010424.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely benign
(Sep 16, 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: SCV002047110.3
First in ClinVar: Jan 01, 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: SCV002551598.6
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: SCV001040497.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Likely benign
(Mar 11, 2022)
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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: SCV004769732.1
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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Likely benign
(Feb 18, 2020)
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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: SCV001185786.4
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
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563279.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Comment:
NTHL1: BS1
Number of individuals with the variant: 9
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Uncertain significance
(Jun 01, 2018)
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no assertion criteria provided
Method: clinical testing
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Familial adenomatous polyposis 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Oncology Laboratory, Hospital Clínico San Carlos
Accession: SCV000844933.1
First in ClinVar: Apr 21, 2019 Last updated: Apr 21, 2019 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550289.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The NTHL1 p.I58T variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP … (more)
The NTHL1 p.I58T variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs1805378) and in ClinVar (classified as uncertain significance by Molecular Oncology Laboratory, Hospital Clínico San Carlos for Familial adenomatous polyposis 3). The variant was also identified in control databases in 500 of 277380 chromosomes (1 homozygous) at a frequency of 0.001803 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 56 of 10282 chromosomes (freq: 0.005446), Latino in 107 of 35394 chromosomes (freq: 0.003023), Other in 17 of 7160 chromosomes (freq: 0.002374), European (non-Finnish) in 279 of 127442 chromosomes (freq: 0.002189), South Asian in 23 of 30596 chromosomes (freq: 0.000752), European (Finnish) in 9 of 21854 chromosomes (freq: 0.000412), African in 7 of 24764 chromosomes (freq: 0.000283), and East Asian in 2 of 19888 chromosomes (freq: 0.000101). The p.Ile58 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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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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Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer. | Adamson AW | Journal of ovarian research | 2023 | PMID: 37460928 |
Lynch syndrome: influence of additional susceptibility variants on cancer risk. | Vibert R | European journal of human genetics : EJHG | 2023 | PMID: 37088804 |
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 |
Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium. | Boulouard F | Clinical genetics | 2021 | PMID: 33454955 |
Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study. | Shickh S | Journal of medical genetics | 2021 | PMID: 32581083 |
Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing. | Lorca V | Scientific reports | 2019 | PMID: 31285513 |
NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. | Belhadj S | Scientific reports | 2019 | PMID: 31227763 |
Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. | Smith CG | Journal of the National Cancer Institute | 2013 | PMID: 23852950 |
Text-mined citations for rs1805378 ...
HelpRecord last updated May 12, 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.