rs138287857

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004655.4(AXIN2):c.2051C>T(p.Ala684Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,800 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A684A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

AXIN2
NM_004655.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:11

Conservation

PhyloP100: 7.55

Variant links:

Genes affected

AXIN2 (HGNC:904): (axin 2) The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. [provided by RefSeq, Jul 2008]

AXIN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010069042).

BP6

Variant 17-65536410-G-A is Benign according to our data. Variant chr17-65536410-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127941.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=2, Uncertain_significance=1}. Variant chr17-65536410-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4 linkuse as main transcript	c.2051C>T	p.Ala684Val	missense_variant	8/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AXIN2	ENST00000307078.10 linkuse as main transcript	c.2051C>T	p.Ala684Val	missense_variant	8/11	1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5 linkuse as main transcript	c.1856C>T	p.Ala619Val	missense_variant	6/9	1		ENSP00000364854
AXIN2	ENST00000618960.4 linkuse as main transcript	c.1856C>T	p.Ala619Val	missense_variant	7/10	5		ENSP00000478916
AXIN2	ENST00000578251.1 linkuse as main transcript	n.273C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

165

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00160

AC:

392

AN:

245102

Hom.:

AF XY:

0.00170

AC XY:

226

AN XY:

133024

show subpopulations

Gnomad AFR exome

AF:

0.000190

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00849

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000361

Gnomad FIN exome

AF:

0.000836

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.00300

GnomAD4 exome

AF:

0.00177

AC:

2588

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1236

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00904

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00108

AC:

165

AN:

152358

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00194

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00180

AC:

218

EpiCase

AF:

0.00164

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2017	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. -

Oligodontia-cancer predisposition syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AXIN2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 05, 2020	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 09, 2019	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. -

Aganglionic megacolon

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Human Genomics Unit, Institute for molecular medicine Finland (FIMM)

- -

Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

Colorectal cancer

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Nov 01, 2017

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. -

AXIN2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

.;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D;.

M_CAP

Benign

0.074

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.16

Sift

Uncertain

0.0090

D;.;D

Sift4G

Benign

0.10

T;D;D

Polyphen

0.92

.;P;P

Vest4

0.55

MVP

0.79

MPC

0.41

ClinPred

0.045

GERP RS

4.4

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over