rs200883019

Positions:

• chr17-65537504-G-A
• chr17-65537504-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004655.4(AXIN2):​c.1532C>T​(p.Thr511Met) variant causes a missense change. The variant allele was found at a frequency of 0.000569 in 1,613,776 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. T511S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 6.10

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0090275705).
• BP6: Variant 17-65537504-G-A is Benign according to our data. Variant chr17-65537504-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 324645.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 156 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1532C>T	p.Thr511Met	missense_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1532C>T	p.Thr511Met	missense_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1532C>T	p.Thr511Met	missense_variant	5/9	1
AXIN2	ENST00000618960.4	c.1532C>T	p.Thr511Met	missense_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 151830 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00124 AC: 312 AN: 251244 Hom.: 0 AF XY: 0.00128 AC XY: 174 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000521 AC: 762 AN: 1461828 Hom.: 1 Cov.: 36 AF XY: 0.000531 AC XY: 386 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.00103 AC: 156 AN: 151948 Hom.: 1 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74230

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000980 AC: 119

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2020	This variant is associated with the following publications: (PMID: 25759019, 23456260) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.24	T;.;T
Sift4G	Benign	0.062	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.73
MVP		0.63
MPC		0.73
ClinPred		0.055	T
GERP RS		5.1
gMVP		0.41

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

Other links and lift over

dbSNP: rs200883019; hg19: chr17-63533622; COSMIC: COSV61057800; COSMIC: COSV61057800;