17-65530080-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_004655.4(AXIN2):c.2428G>A(p.Asp810Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,614,174 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts 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. D810H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 5.01

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 Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-65530080-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1422755.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012767017).
• BP6: Variant 17-65530080-C-T is Benign according to our data. Variant chr17-65530080-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127945.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (175/152306) while in subpopulation AFR AF= 0.00392 (163/41568). AF 95% confidence interval is 0.00343. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.2428G>A	p.Asp810Asn	missense_variant	11/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.2428G>A	p.Asp810Asn	missense_variant	11/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.2233G>A	p.Asp745Asn	missense_variant	9/9	1
AXIN2	ENST00000618960.4	c.2233G>A	p.Asp745Asn	missense_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.000956

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251282 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135850

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 236 AN: 1461868 Hom.: 2 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727240

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74466

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.00134

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 23, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 15, 2019	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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2018

This variant is denoted AXIN2 c.2428G>A at the cDNA level, p.Asp810Asn (D810N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant was observed in at least one individual with breast or gynecological cancer, as well as individuals with colon cancer (DeRycke 2017, Dominguez-Valentin 2018). AXIN2 Asp810Asn was observed at an allele frequency of 0.35% (83/24,028) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the DIX domain (Salahshor 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether AXIN2 Asp810Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Oligodontia-cancer predisposition syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

AXIN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2021

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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Benign	0.13
Sift	Benign	0.13	T;.;D
Sift4G	Benign	0.086	T;T;T
Polyphen		0.14	.;B;B
Vest4		0.25
MVP		0.39
MPC		0.21
ClinPred		0.063	T
GERP RS		3.6
gMVP		0.35

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: rs140344858; hg19: chr17-63526198; COSMIC: COSV61055908; COSMIC: COSV61055908;