rs1060502149

Positions:

• chr17-65557871-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004655.4(AXIN2):​c.750G>T​(p.Leu250Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.760

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34265903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.750G>T	p.Leu250Phe	missense_variant	2/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.750G>T	p.Leu250Phe	missense_variant	2/11	1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5	c.750G>T	p.Leu250Phe	missense_variant	1/9	1		ENSP00000364854
AXIN2	ENST00000618960.4	c.750G>T	p.Leu250Phe	missense_variant	2/10	5		ENSP00000478916
AXIN2	ENST00000577278.1	c.750G>T	p.Leu250Phe	missense_variant	2/2	5		ENSP00000464264

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 250 of the AXIN2 protein (p.Leu250Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408834). 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 with a positive predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2022

The p.L250F variant (also known as c.750G>T), located in coding exon 1 of the AXIN2 gene, results from a G to T substitution at nucleotide position 750. The leucine at codon 250 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was detected in 1/224 unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.37	.;T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D;.;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;.;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;.;D;.
Sift4G	Uncertain	0.0090	D;D;D;.
Polyphen		1.0	.;D;D;.
Vest4		0.79
MutPred		0.33		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.65
MPC		0.29
ClinPred		0.70	D
GERP RS		3.1
gMVP		0.53

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: rs1060502149; hg19: chr17-63553989;