17-65536509-G-C

Position:

• chr17-65536509-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004655.4(AXIN2):​c.1952C>G​(p.Ser651Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. S651L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.889

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17952365).
• BS2: High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1952C>G	p.Ser651Trp	missense_variant	8/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1952C>G	p.Ser651Trp	missense_variant	8/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1757C>G	p.Ser586Trp	missense_variant	6/9	1
AXIN2	ENST00000618960.4	c.1757C>G	p.Ser586Trp	missense_variant	7/10	5
AXIN2	ENST00000578251.1	n.174C>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461490 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 727026

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: 0.0000315

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2023	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 22, 2021	- -

Oligodontia-cancer predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 651 of the AXIN2 protein (p.Ser651Trp). 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: 464586). 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 not expected to disrupt AXIN2 protein function with a negative 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. -

Colorectal cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 20, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 18, 2022

The AXIN2 c.1952C>G; p.Ser651Trp variant (rs74006838), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 464586). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The serine at codon 651 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.184). Due to limited information, the clinical significance of the p.Ser651Trp variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.0
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.80	.;T;.
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Benign	0.18
Sift	Benign	0.11	T;.;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.77	.;P;P
Vest4		0.33
MutPred		0.28		Loss of phosphorylation at S651 (P = 0.0054);.;.;
MVP		0.099
MPC		0.64
ClinPred		0.56	D
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20

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: rs74006838; hg19: chr17-63532627;