rs149764887

chr17-65537351-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004655.4(AXIN2):c.1685C>T(p.Pro562Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,614,122 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. P562S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: -0.376

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013717681).
• BP6: Variant 17-65537351-G-A is Benign according to our data. Variant chr17-65537351-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127937.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3, Benign=2}. Variant chr17-65537351-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1685C>T	p.Pro562Leu	missense_variant	6/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1685C>T	p.Pro562Leu	missense_variant	6/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1685C>T	p.Pro562Leu	missense_variant	5/9	1
AXIN2	ENST00000618960.4	c.1685C>T	p.Pro562Leu	missense_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000603

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000336 AC: 84 AN: 249918 Hom.: 0 AF XY: 0.000340 AC XY: 46 AN XY: 135226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000489 AC: 715 AN: 1461864 Hom.: 0 Cov.: 36 AF XY: 0.000514 AC XY: 374 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000615

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74434

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000654

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with primary melanoma but also in healthy controls (Pedace 2011); This variant is associated with the following publications: (PMID: 21294210, 26224873, 27739435, 28717660) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	AXIN2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Oligodontia-cancer predisposition syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2022	Variant summary: AXIN2 c.1685C>T (p.Pro562Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 249918 control chromosomes (gnomAD), predominantly at a frequency of 0.00064 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1685C>T has been reported in the literature in individuals of Non-Finnish European ancestry affected tooth agenesis (Keskin_2021), Colorectal Cancer (Chan_2021), and Breast Cancer (Moradian_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 2018	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. -

AXIN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2023

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	0.056
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.18
Dann	Benign	0.71
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.087	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.57	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.60	T;.;T
Sift4G	Benign	0.85	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.075
MVP		0.085
MPC		0.18
ClinPred		0.026	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.16

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: rs149764887; hg19: chr17-63533469;