rs201531372

Variant names:

• chr17-65557998-G-A
• rs201531372
• NM_004655.4:c.623C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65557998-G-A
• chr17-65557998-G-C
• chr17-65557998-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004655.4(AXIN2):​c.623C>T​(p.Ala208Val) variant causes a missense change. The variant allele was found at a frequency of 0.000194 in 1,614,160 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 4.47
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• oligodontia-cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• craniosynostosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000266076 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066269994).
• BP6: Variant 17-65557998-G-A is Benign according to our data. Variant chr17-65557998-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127947.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00025 (38/152266) while in subpopulation AMR AF = 0.000654 (10/15302). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.623C>T	p.Ala208Val	missense_variant	Exon 2 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.623C>T	p.Ala208Val	missense_variant	Exon 2 of 11	1	NM_004655.4	ENSP00000302625.5
ENSG00000266076	ENST00000577662.1	n.*799C>T		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000462418.1
ENSG00000266076	ENST00000577662.1	n.*799C>T		3_prime_UTR_variant	Exon 4 of 7	2		ENSP00000462418.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251478 AF XY: 0.000250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1461894 Hom.: 2 Cov.: 31 AF XY: 0.000216 AC XY: 157 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1112012

Other (OTH) AF: 0.000414 AC: 25 AN: 60396

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74446

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Nov 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of colorectal and other cancers (PMID: 28577310, 28944238, 29212164); This variant is associated with the following publications: (PMID: 29641532, 28944238, 29212164, 28577310) -

Jul 06, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AXIN2 p.Ala208Val variant was identified in dbSNP (ID: rs201531372), ClinVar (classified as likely benign by Illumina and as a VUS by GeneDx and Invitae for Oligodontia-colorectal cancer syndrome) and LOVD 3.0 but was not found in Cosmic. The variant was identified in control databases in 63 of 282882 chromosomes at a frequency of 0.000223 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 25 of 30616 chromosomes (freq: 0.000817), Other in 3 of 7228 chromosomes (freq: 0.000415), Latino in 8 of 35440 chromosomes (freq: 0.000226), European (non-Finnish) in 25 of 129186 chromosomes (freq: 0.000194), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004); it was not observed in the African and East Asian populations. The c.623C>T variant was identified somatically in one patient affected with Lynch Syndrome (Vargas-Parra_2017_PMID: 28566310). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ala208 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant canont be determined with certainty at this time. The variant is classified as a variant of uncertain significance. -

not specified Uncertain:1 Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AXIN2 c.623C>T (p.Ala208Val) 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 0.00024 in 251478 control chromosomes, predominantly at a frequency of 0.00082 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing colorectal cancer (0.00014), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.623C>T has been reported in the literature in settings of multigene panel testing in individuals affected with colorectal cancer, without strong evidence for causality (e.g. Vargas-Parra_2017, DeRycke_2017, Raskin_2017). These reports do not provide unequivocal conclusions about association of the variant with colorectal cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as either benign (n=1) or likely benign (n=3), and the others classified the variant as VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Oligodontia-cancer predisposition syndrome Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:2

Jun 22, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 27, 2023

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. -

AXIN2-related disorder Benign:1

Jan 02, 2024

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	0.081
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.32	.;T;T;T
Eigen	Benign	0.046
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	.;D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-0.77	T
PhyloP100		4.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.19	T;.;T;.
Sift4G	Benign	0.17	T;T;T;.
Polyphen		0.15	.;B;B;.
Vest4		0.54
MVP		0.62
MPC		0.55
ClinPred		0.083	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.52
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs201531372; hg19: chr17-63554116;