rs768265778

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1BS2

The NM_004655.4(AXIN2):c.-12_8delAGCTCCCTCACCATGAGTAG(p.Met1fs) variant causes a frameshift, start lost change. The variant allele was found at a frequency of 0.0000124 in 1,606,462 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AXIN2
NM_004655.4 frameshift, start_lost

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 7.13

Publications

1 publications found

Variant links:

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]

AXIN2 Gene-Disease associations (from GenCC):

oligodontia-cancer predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
craniosynostosis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

AXIN2 links:

ENSG00000266076 (HGNC:):

ENSG00000266076 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 176 pathogenic variants in the truncated region.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4 link	c.-12_8delAGCTCCCTCACCATGAGTAG	p.Met1fs	frameshift_variant, start_lost	Exon 2 of 11	ENST00000307078.10	NP_004646.3	Q9Y2T1
AXIN2	NM_004655.4 link	c.-12_8delAGCTCCCTCACCATGAGTAG		5_prime_UTR_variant	Exon 2 of 11	ENST00000307078.10	NP_004646.3	Q9Y2T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AXIN2	ENST00000307078.10 link	c.-12_8delAGCTCCCTCACCATGAGTAG	p.Met1fs	frameshift_variant, start_lost	Exon 2 of 11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
ENSG00000266076	ENST00000577662.1 link	n.165_184delAGCTCCCTCACCATGAGTAG		non_coding_transcript_exon_variant	Exon 4 of 7	2		ENSP00000462418.1	J3KSC3
AXIN2	ENST00000307078.10 link	c.-12_8delAGCTCCCTCACCATGAGTAG		5_prime_UTR_variant	Exon 2 of 11	1	NM_004655.4	ENSP00000302625.5	Q9Y2T1
ENSG00000266076	ENST00000577662.1 link	n.165_184delAGCTCCCTCACCATGAGTAG		3_prime_UTR_variant	Exon 4 of 7	2		ENSP00000462418.1	J3KSC3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000828

AC:

AN:

241688

AF XY:

0.00000757

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1454322

Hom.:

AF XY:

0.0000111

AC XY:

AN XY:

723876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111896

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Deletion involving the initiation codon in a gene for which a downstream in-frame ATG could serve as an alternate initiator codon; Observed in an individual with breast cancer (PMID: 26681312); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15611123, 26681312, 36502525) -

Dec 26, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The AXIN2 c.-12_8del; p.Met1? variant (rs768265778) is reported in the literature in at least one individual affected with breast cancer (Susswein 2016). This variant is also reported in ClinVar (Variation ID: 239971), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes loss of the canonical initiator methionine codon by deleting 12 nucleotides upstream of the ATG start site and 8 nucleotides of the coding region. While this variant is predicted to disrupt protein translation from the normal start site, there is an alternate in-frame methionine located just downstream. However, without functional studies, the effect of this variant on translation is unknown. Due to limited information, the clinical significance of the c.-12_8del; p.Met1? variant is uncertain at this time. References: Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. -

Dec 05, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The AXIN2 c.-12_8del variant disrupts the translation initiation codon of the AXIN2 mRNA and is predicted to interfere with AXIN2 protein synthesis, however there is alternate in-frame methionine located downstream at the 5th codon that results in a biologically relevant transcript. In the published literature, this variant has been reported in individuals with colorectal polyps and intestinal cancer (PMID: 36502525 (2022)) and breast cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.0000083 (2/241688 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Oligodontia-cancer predisposition syndrome;C5680012:AXIN2-related attenuated familial adenomatous polyposis

Pathogenic:1

Feb 01, 2021

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oligodontia-cancer predisposition syndrome

Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the AXIN2 mRNA. The next in-frame methionine is located at codon 5. This variant is present in population databases (rs768265778, gnomAD 0.007%). Disruption of the initiator codon has been observed in individual(s) with clinical features of AXIN2-related conditions (PMID: 26681312, 36502525). ClinVar contains an entry for this variant (Variation ID: 239971). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Mar 05, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-12_8del20 variant (also known as p.M1?) is located in coding exon 1 of the AXIN2 gene and results from a deletion of 20 nucleotides at positions c.-12 to c.8. This removes the methionine residue at the initiation codon. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This variant has been reported in a French family with oligodontia (Leclerc J et al. Genes Chromosomes Cancer. 2023 Apr;62(4):210-222). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with AXIN2-related disease but also in unaffected individuals (Ambry internal data). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 4 amino acids from the initiation site, which may result in N-terminal truncation of unknown significance. 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

PhyloP100

7.1

Mutation Taster

=4/196

disease causing (long InDel)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over