rs1064793954

Positions:

• chr17-65537639-G-A
• chr17-65537639-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004655.4(AXIN2):​c.1397C>T​(p.Ser466Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S466C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.35

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1397C>T	p.Ser466Phe	missense_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1397C>T	p.Ser466Phe	missense_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1397C>T	p.Ser466Phe	missense_variant	5/9	1
AXIN2	ENST00000618960.4	c.1397C>T	p.Ser466Phe	missense_variant	6/10	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426766 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 707018

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AXIN2 protein function. ClinVar contains an entry for this variant (Variation ID: 419561). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 466 of the AXIN2 protein (p.Ser466Phe). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2018

This variant is denoted AXIN2 c.1397C>T at the cDNA level, p.Ser466Phe (S466F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. AXIN2 Ser466Phe was not observed in large population cohorts (Lek 2016). This variant is located in the beta catenin binding domain (Salahshor 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether AXIN2 Ser466Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The p.S466F variant (also known as c.1397C>T), located in coding exon 5 of the AXIN2 gene, results from a C to T substitution at nucleotide position 1397. The serine at codon 466 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

AXIN2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2023

The AXIN2 c.1397C>T variant is predicted to result in the amino acid substitution p.Ser466Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.0034	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.71
MutPred		0.46		Loss of phosphorylation at S466 (P = 0.0095);Loss of phosphorylation at S466 (P = 0.0095);Loss of phosphorylation at S466 (P = 0.0095);
MVP		0.75
MPC		0.74
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.54

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: rs1064793954; hg19: chr17-63533757;