chr17-65536410-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

2
5
11

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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: {Uncertain_significance=1, Benign=2, Likely_benign=8}. Variant chr17-65536410-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (165/152358) while in subpopulation NFE AF= 0.00156 (106/68028). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 165 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.2051C>T p.Ala684Val missense_variant Exon 8 of 11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.2051C>T p.Ala684Val missense_variant Exon 8 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
AXIN2ENST00000375702.5 linkc.1856C>T p.Ala619Val missense_variant Exon 6 of 9 1 ENSP00000364854.5 E7ES00
AXIN2ENST00000618960.4 linkc.1856C>T p.Ala619Val missense_variant Exon 7 of 10 5 ENSP00000478916.1 E7ES00
AXIN2ENST00000578251.1 linkn.273C>T non_coding_transcript_exon_variant Exon 1 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.00108
AC:
165
AN:
152240
Hom.:
0
Cov.:
33
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.:
0
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.:
6
Cov.:
33
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.:
0
Cov.:
33
AF XY:
0.000953
AC XY:
71
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.:
0
Bravo
AF:
0.00103
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000682
AC:
3
ESP6500EA
AF:
0.00174
AC:
15
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
Dec 21, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 15, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oligodontia-cancer predisposition syndrome Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Benign:2
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

AXIN2: BP4, BS1 -

Mar 19, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Mar 24, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Sep 09, 2019
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Hirschsprung disease Pathogenic:1
-
Human Genomics Unit, Institute for molecular medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Colorectal cancer;C1837750:Oligodontia-cancer predisposition syndrome Benign:1
Mar 04, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer Benign:1
Nov 01, 2017
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

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
Feb 26, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.39
.;T;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
.;D;.
M_CAP
Benign
0.074
D
MetaRNN
Benign
0.010
T;T;T
MetaSVM
Benign
-0.58
T
PrimateAI
Uncertain
0.49
T
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
T
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.

Other links and lift over

dbSNP: rs138287857; hg19: chr17-63532528; COSMIC: COSV61057901; COSMIC: COSV61057901; API