rs906309952

Positions:

• chr17-65538342-C-T

Variant summary

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

The NM_004655.4(AXIN2):​c.1061G>A​(p.Arg354Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AXIN2 NM_004655.4 missense, splice_region
• Scores: Splicing: ADA: 0.9846
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.08

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1061G>A	p.Arg354Lys	missense_variant, splice_region_variant	5/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1061G>A	p.Arg354Lys	missense_variant, splice_region_variant	5/11	1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5	c.1061G>A	p.Arg354Lys	missense_variant, splice_region_variant	4/9	1		ENSP00000364854
AXIN2	ENST00000618960.4	c.1061G>A	p.Arg354Lys	missense_variant, splice_region_variant	5/10	5		ENSP00000478916

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

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

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 354 of the AXIN2 protein (p.Arg354Lys). 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: 565786). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Colorectal cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 06, 2024

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15735151) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The p.R354K variant (also known as c.1061G>A), located in coding exon 4 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1061. The arginine at codon 354 is replaced by lysine, an amino acid with highly similar 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D;.
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	D;.;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.028	.;B;B
Vest4		0.86
MutPred		0.38		Gain of methylation at R354 (P = 0.0123);Gain of methylation at R354 (P = 0.0123);Gain of methylation at R354 (P = 0.0123);
MVP		0.66
MPC		0.20
ClinPred		0.95	D
GERP RS		5.3
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.87
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: rs906309952; hg19: chr17-63534460; COSMIC: COSV100196580; COSMIC: COSV100196580;