VCV000127943.62 - ClinVar

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

Germline

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.

(18)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(3); Likely benign(7)

criteria provided, conflicting classifications

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: VCV000127943.62

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 13, 2025	Dec 2, 2024

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

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

The Genome Aggregation Database (gnomAD) 0.00179

The Genome Aggregation Database (gnomAD), exomes 0.00192

Exome Aggregation Consortium (ExAC) 0.00240

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00284

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00176

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	3866	3880

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 interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Dec 2, 2024	RCV000115875.18
Oligodontia-cancer predisposition syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000205073.26
not specified	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 31, 2024	RCV000212102.31
Colorectal cancer Oligodontia	Likely benign (1)	no assertion criteria provided	Aug 1, 2016	RCV000417339.10
not provided	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Nov 1, 2024	RCV000586946.39
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.	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 benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Oligodontia-cancer predisposition syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000405679.3 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). 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)
Likely benign (Jul 30, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537167.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Mar 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149784.16 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 26406231, 21626677, 24581859, 25186949, 27090353, 25801821, 27365112, 29371908, 29772684)
Likely benign (Nov 03, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001473768.3 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Oligodontia-cancer predisposition syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261931.10 First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024
Uncertain significance (Feb 04, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000266997.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Likely benign (Aug 17, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	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: 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 … (more) 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)
Benign (Jun 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069068.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Oct 22, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	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
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	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
Uncertain significance (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551230.7 First in ClinVar: Jul 30, 2022 Last updated: Aug 04, 2024
Likely benign (Nov 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004138831.11 First in ClinVar: Nov 20, 2023 Last updated: Dec 22, 2024	Comment: AXIN2: BP4, BS1 Number of individuals with the variant: 10
Likely benign (Dec 02, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001175793.5 First in ClinVar: Mar 16, 2020 Last updated: Jan 13, 2025	Publications: PubMed (2) PubMed: 21626677‚ 29371908 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)
Likely benign (Oct 25, 2019)	no assertion criteria provided Method: clinical testing	AXIN2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004749459.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 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).
Likely benign (Aug 01, 2016)	no assertion criteria provided Method: research	Colorectal cancer oligodontia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	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: 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 … (more) 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)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691772.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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
not provided (-)	no classification provided Method: phenotyping only	Not provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000840120.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: 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 … (more) 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) Clinical Features: Abnormality of the large intestine (present) , Abnormality of the intestine (present) , Feeding difficulties (present) Indication for testing: Presymptomatic 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
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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:

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 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.

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:

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 13, 2025

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

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145007501 ...