rs1064796197

chr17-65557866-CT-GG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004655.4(AXIN2):c.754_755delinsCC(p.Ser252Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S252C) has been classified 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:3
• Conservation: PhyloP100: 5.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.754_755delinsCC	p.Ser252Pro	missense_variant	2/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.754_755delinsCC	p.Ser252Pro	missense_variant	2/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.754_755delinsCC	p.Ser252Pro	missense_variant	1/9	1
AXIN2	ENST00000577278.1	c.754_755delinsCC	p.Ser252Pro	missense_variant	2/2	5
AXIN2	ENST00000618960.4	c.754_755delinsCC	p.Ser252Pro	missense_variant	2/10	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2017

This variant is denoted AXIN2 c.754_755delAGinsCC at the cDNA level, p.Ser252Pro (S252P) at the protein level. The normal sequence, with the bases that are altered in brackets, is GTCC[delAG][insCC]CAAA. This in frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Serine to a Proline (AGC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Neither AXIN2 c.754_755delAGinsCC nor AXIN2 Ser252Pro (by this or an alternate nucleotide change) was observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. AXIN2 Ser252Pro occurs at a position that is conserved in mammals and is not located in a known functional domain (Salahshor 2005). Based on currently available evidence, it is unclear whether AXIN2 Ser252Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Oligodontia-cancer predisposition syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 423052). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 252 of the AXIN2 protein (p.Ser252Pro). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.754_755delAGinsCC variant (also known as p.S252P), located in coding exon 1 of the AXIN2 gene, results from an in-frame deletion of AG and insertion of CC at nucleotide positions 754 to 755. This results in the substitution of the serine residue for a proline residue at codon 252, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064796197; hg19: chr17-63553984;