ClinVar Genomic variation as it relates to human health
NM_004655.4(AXIN2):c.2051C>T (p.Ala684Val)
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(1); Benign(2); Likely benign(9)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004655.4(AXIN2):c.2051C>T (p.Ala684Val)
Variation ID: 127941 Accession: VCV000127941.53
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q24.1 17: 65536410 (GRCh38) [ NCBI UCSC ] 17: 63532528 (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 Dec 6, 2016 May 1, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004655.4:c.2051C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004646.3:p.Ala684Val missense NM_001363813.1:c.1856C>T NP_001350742.1:p.Ala619Val missense NC_000017.11:g.65536410G>A NC_000017.10:g.63532528G>A NG_012142.1:g.30213C>T LRG_296:g.30213C>T LRG_296t1:c.2051C>T - Protein change
- A684V, A619V
- Other names
- p.A684V:GCG>GTG
- Canonical SPDI
- NC_000017.11:65536409: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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00112
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00138
The Genome Aggregation Database (gnomAD), exomes 0.00160
Exome Aggregation Consortium (ExAC) 0.00187
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
Trans-Omics for Precision Medicine (TOPMed) 0.00103
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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AXIN2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3587 | 3601 |
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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Feb 6, 2024 | RCV000115873.23 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000234519.24 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 1, 2017 | RCV000735972.10 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV000736045.9 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Mar 24, 2021 | RCV001014207.11 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 4, 2022 | RCV002490780.8 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000857937.28 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 26, 2020 | RCV003935106.1 |
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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Benign
(Feb 15, 2019)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698519.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: AXIN2 c.2051C>T (p.Ala684Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: AXIN2 c.2051C>T (p.Ala684Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 274154 control chromosomes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is benign. c.2051C>T has been reported in the literature in individuals affected with non-sydromic isolated oligodontia, bicuspid aortic valve, colorectal cancer, cutaneous melanoma (Bergendal_2011, Bonachea_2014, Rohlin_2017, Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. Co-occurrence with other pathogenic variant has been reported (DNMT3A c.2645G>A, p.Arg882His), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign (1x benign, 3x likely benign). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Oligodontia-cancer predisposition syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000405686.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Mar 05, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474513.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely benign
(Mar 24, 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: SCV002537145.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Sep 09, 2019)
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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: SCV001174889.4
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
(Dec 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149782.14
First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Likely benign
(Nov 01, 2017)
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criteria provided, single submitter
Method: research
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Colorectal cancer
Affected status: yes
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: CSER - NEXT Medicine variant annotation
Accession: SCV000864161.1 First in ClinVar: Jan 12, 2019 Last updated: Jan 12, 2019 |
Comment:
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 33 year old female diagnosed with colon … (more)
Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 33 year old female diagnosed with colon cancer at age 32. Family history of colorectal cancer or colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. (less)
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Likely benign
(Mar 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Oligodontia-cancer predisposition syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002799272.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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: SCV002551239.6
First in ClinVar: Jul 30, 2022 Last updated: Feb 14, 2024 |
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Oligodontia-cancer predisposition syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000288690.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Likely benign
(Feb 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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AXIN2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004752990.1
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 01, 2024)
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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: SCV001151402.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Comment:
AXIN2: BP4, BS1
Number of individuals with the variant: 9
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Hirschsprung disease
Affected status: yes
Allele origin:
unknown
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Human Genomics Unit, Institute for molecular medicine Finland (FIMM)
Accession: SCV000845745.1
First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 |
Number of individuals with the variant: 1
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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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Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. | Rohlin A | Familial cancer | 2017 | PMID: 27696107 |
Use of a targeted, combinatorial next-generation sequencing approach for the study of bicuspid aortic valve. | Bonachea EM | BMC medical genomics | 2014 | PMID: 25260786 |
Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. | Bergendal B | American journal of medical genetics. Part A | 2011 | PMID: 21626677 |
Text-mined citations for rs138287857 ...
HelpRecord last updated May 01, 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.