VCV000127943.74 - ClinVar

NM_004655.4(AXIN2):c.2272G>A (p.Ala758Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(3); Likely benign(9)

14 out of 19 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004655.4(AXIN2):c.2272G>A (p.Ala758Thr)

Variation ID: 127943 Accession: VCV000127943.74

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q24.1 17: 65534045 (GRCh38) [ NCBI UCSC ] 17: 63530163 (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	Apr 13, 2016	Jan 11, 2026	Sep 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_004655.4:c.2272G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004646.3:p.Ala758Thr	missense
NM_001363813.1:c.2077G>A	NP_001350742.1:p.Ala693Thr	missense
NC_000017.11:g.65534045C>T
NC_000017.10:g.63530163C>T
NG_012142.1:g.32578G>A
LRG_296:g.32578G>A
LRG_296t1:c.2272G>A

... more HGVS ... less HGVS

Protein change

A758T, A693T

Other names

p.A758T:GCG>ACG

Canonical SPDI

NC_000017.11:65534044:C:T

Global minor allele frequency (GMAF) Help The 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.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

The Genome Aggregation Database (gnomAD) 0.00175

Trans-Omics for Precision Medicine (TOPMed) 0.00176

The Genome Aggregation Database (gnomAD) 0.00179

The Genome Aggregation Database (gnomAD), exomes 0.00192

Exome Aggregation Consortium (ExAC) 0.00240

The Genome Aggregation Database (gnomAD), exomes 0.00273

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00284

Links

ClinGen: CA288104 dbSNP: rs145007501 VarSome

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
Gene	OMIM	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.
AXIN2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4188	4202

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.
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Dec 2, 2024	RCV000115875.19
Oligodontia-cancer predisposition syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 4, 2025	RCV000205073.28
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Mar 4, 2025	RCV000212102.33
Colorectal cancer Oligodontia	Likely benign (1)	no assertion criteria provided	Aug 1, 2016	RCV000417339.10
not provided	Conflicting classifications of pathogenicity (7)	criteria provided, conflicting classifications	Sep 1, 2025	RCV000586946.51
AXIN2-related disorder	Likely benign (1)	no assertion criteria provided	Oct 25, 2019	RCV004529936.2

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Feb 04, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Vantari Genetics Accession: SCV000266997.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Aug 17, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not provided	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698520.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (1) PubMed: 21626677 Comment: show Variant summary: The AXIN2 c.2272G>A (p.Ala758Thr) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 291/121600 (1/417), which exceeds the estimated maximal expected allele frequency for a pathogenic AXIN2 variant of 1/7037, suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in an affected individual with tooth agenesis, but had no family history of colorectal cancer. However, tooth agenesis has been implicated as a precursor for cancer, although this cannot be established for the current variant due to limited available information. Multiple clinical laboratories cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, until additional information becomes available the variant of interest has been classified as Likely Benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Apr 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Oligodontia-cancer predisposition syndrome	Illumina Laboratory Services, Illumina Accession: SCV000405679.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jun 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Genetic Services Laboratory, University of Chicago Accession: SCV002069068.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely benign (Jul 30, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary cancer-predisposing syndrome	Sema4, Sema4 Accession: SCV002537167.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (Oct 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not specified	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002773957.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (2) PubMed: 29371908‚ 21626677 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely benign (Mar 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV000149784.16 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: show This variant is associated with the following publications: (PMID: 26406231, 21626677, 24581859, 25186949, 27090353, 25801821, 27365112, 29371908, 29772684) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009783.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided

Likely benign (Dec 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV001175793.5 First in ClinVar: Mar 16, 2020 Last updated: Jan 13, 2025	Publications: PubMed (2) PubMed: 21626677‚ 29371908 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Feb 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Oligodontia-cancer predisposition syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261931.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 16, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551230.8 First in ClinVar: Jul 30, 2022 Last updated: Mar 11, 2025	Publications: PubMed (1) PubMed: 21626677 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Sep 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV004138831.20 First in ClinVar: Nov 20, 2023 Last updated: Jan 11, 2026	Comment: show AXIN2: BP4, BS1 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 15

Likely Benign (Mar 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001473768.4 First in ClinVar: Jan 26, 2021 Last updated: Mar 11, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jan 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Oligodontia-cancer predisposition syndrome	Myriad Genetics, Inc. Accession: SCV006095871.1 First in ClinVar: Jun 22, 2025 Last updated: Jun 22, 2025	Comment: show This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely benign (Aug 01, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Colorectal cancer oligodontia (Autosomal dominant inheritance)	CSER _CC_NCGL, University of Washington Study: CSER - NEXT Medicine variant annotation Accession: SCV000503519.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: show Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 19 year old with a history of a tubulovillous adenoma at age 16. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691772.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	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: SCV001970538.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Oct 25, 2019) N Not contributing to aggregate classification	no assertion criteria provided	AXIN2-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004749459.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show 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). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	Not provided	GenomeConnect, ClinGen Accession: SCV000840120.2 First in ClinVar: Oct 13, 2018 Last updated: Apr 13, 2025	Comment: show GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation: 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown more Observation 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Abnormality of the large intestine (present) , Abnormality of the intestine (present) , Feeding difficulties (present) Indication for testing: Presymptomatic Test name: Gene Panel Sequencing Age: 40-49 years Sex: female Ethnicity/Population group: Caucasians MedGen:C0043157 Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-04-06 Testing laboratory interpretation: Uncertain significance

Comment:

Variant summary: The AXIN2 c.2272G>A (p.Ala758Thr) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 291/121600 (1/417), which exceeds the estimated maximal expected allele frequency for a pathogenic AXIN2 variant of 1/7037, suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in an affected individual with tooth agenesis, but had no family history of colorectal cancer. However, tooth agenesis has been implicated as a precursor for cancer, although this cannot be established for the current variant due to limited available information. Multiple clinical laboratories cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, until additional information becomes available the variant of interest has been classified as Likely Benign.

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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds.	Dominguez-Valentin M	Hereditary cancer in clinical practice	2018	PMID: 29371908
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 rs145007501 ...

These 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 Jan 11, 2026

ClinVar Genomic variation as it relates to human health

NM_004655.4(AXIN2):c.2272G>A (p.Ala758Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs145007501 ...