chr17-65537614-A-ATGG

Position:

• chr17-65537614-A-ATGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004655.4(AXIN2):​c.1419_1421dupCCA​(p.His474dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,580,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: AXIN2 NM_004655.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 0.584

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 -5 ACMG points.

• BP6: Variant 17-65537614-A-ATGG is Benign according to our data. Variant chr17-65537614-A-ATGG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234272.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=6, Uncertain_significance=5}.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1419_1421dupCCA	p.His474dup	disruptive_inframe_insertion	6/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1419_1421dupCCA	p.His474dup	disruptive_inframe_insertion	6/11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1419_1421dupCCA	p.His474dup	disruptive_inframe_insertion	5/9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1419_1421dupCCA	p.His474dup	disruptive_inframe_insertion	6/10	5		ENSP00000478916.1

Frequencies

GnomAD3 genomes AF: 0.000442 AC: 67 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000663

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000302 AC: 63 AN: 208906 Hom.: 0 AF XY: 0.000275 AC XY: 31 AN XY: 112800

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.0000684

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000627

Gnomad SAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.0000700

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.000562

GnomAD4 exome AF: 0.000556 AC: 794 AN: 1428892 Hom.: 0 Cov.: 37 AF XY: 0.000535 AC XY: 380 AN XY: 709644

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.0000970

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0000713

Gnomad4 FIN exome AF: 0.000146

Gnomad4 NFE exome AF: 0.000684

Gnomad4 OTH exome AF: 0.000287

GnomAD4 genome AF: 0.000441 AC: 67 AN: 151784 Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74146

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000474

Gnomad4 NFE AF: 0.000663

Gnomad4 OTH AF: 0.000473

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AXIN2: BP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 04, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	The AXIN2 c.1419_1421dup; p.His474dup variant (rs570443161), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 234272). This variant is observed in the general population with an overall allele frequency of 0.03% (74/240142 alleles) in the Genome Aggregation Database (v2.1.1). This variant inserts a single histidine residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of this variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	This variant is associated with the following publications: (PMID: 28944238, 30404791, 27535533) -

Oligodontia-cancer predisposition syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 05, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2022	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

AXIN2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs570443161; hg19: chr17-63533732;