NM_004655.4(AXIN2):c.2272G>A (p.Ala758Thr) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Nov 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000586946.39

Allele description [Variation Report for NM_004655.4(AXIN2):c.2272G>A (p.Ala758Thr)]

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

Gene:

AXIN2:axin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q24.1

Genomic location:

Preferred name:

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

Other names:

p.A758T:GCG>ACG

HGVS:

NC_000017.11:g.65534045C>T
NG_012142.1:g.32578G>A
NM_001363813.1:c.2077G>A
NM_004655.4:c.2272G>AMANE SELECT
NP_001350742.1:p.Ala693Thr
NP_004646.3:p.Ala758Thr
LRG_296t1:c.2272G>A
LRG_296:g.32578G>A
NC_000017.10:g.63530163C>T
NM_004655.3:c.2272G>A

Protein change:

A693T

Links:

dbSNP: rs145007501

NCBI 1000 Genomes Browser:

rs145007501

Molecular consequence:

NM_001363813.1:c.2077G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004655.4:c.2272G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149784	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Mar 1, 2021)	germline	clinical testing	Citation Link,
SCV000698520	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 17, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000840120	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV001473768	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely benign (Nov 3, 2023)	germline	clinical testing	Citation Link,
SCV001970538	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV002009783	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004138831	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Nov 1, 2024)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	10	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasians MedGen:C0043157	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes.

Bergendal B, Klar J, Stecksén-Blicks C, Norderyd J, Dahl N.

Am J Med Genet A. 2011 Jul;155A(7):1616-22. doi: 10.1002/ajmg.a.34045. Epub 2011 May 27.

PubMed [citation]

PMID:: 21626677

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000149784.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is associated with the following publications: (PMID: 26406231, 21626677, 24581859, 25186949, 27090353, 25801821, 27365112, 29371908, 29772684)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698520.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect, ClinGen, SCV000840120.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasians MedGen:C0043157	not provided	not provided	not provided	phenotyping only	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	validation		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473768.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001970538.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009783.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004138831.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	not provided

Description

AXIN2: BP4, BS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		10	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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