rs139871607

chr17-65538235-T-C

Variant summary

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

The NM_004655.4(AXIN2):c.1168A>G(p.Ser390Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,190 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. S390I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 2.50

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=0.019017488).
• BP6: Variant 17-65538235-T-C is Benign according to our data. Variant chr17-65538235-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127934.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=2, Uncertain_significance=1}. Variant chr17-65538235-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.1168A>G	p.Ser390Gly	missense_variant	5/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.1168A>G	p.Ser390Gly	missense_variant	5/11	1	NM_004655.4	P1
AXIN2	ENST00000375702.5	c.1168A>G	p.Ser390Gly	missense_variant	4/9	1
AXIN2	ENST00000618960.4	c.1168A>G	p.Ser390Gly	missense_variant	5/10	5

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000734 AC: 184 AN: 250828 Hom.: 0 AF XY: 0.000693 AC XY: 94 AN XY: 135674

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00107 AC: 1559 AN: 1461862 Hom.: 2 Cov.: 38 AF XY: 0.00106 AC XY: 770 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74492

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000729

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.000914 AC: 111

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 09, 2021	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	AXIN2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 27300758, 30374176) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 10, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AXIN2 p.Ser390Gly variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs139871607) and ClinVar (classified as likely benign by Illumina, Invitae and the University of Washington Department of Laboratory Medicine and as uncertain significance by GeneDx, Mayo Clinic Genetic Testing Laboratories and the CSER_CC_NCGL; University of Washington Medical Center). The variant was also identified in control databases in 210 of 282220 chromosomes at a frequency of 0.000744 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 183 of 128706 chromosomes (freq: 0.001422), Other in 7 of 7206 chromosomes (freq: 0.000971), European (Finnish) in 8 of 25094 chromosomes (freq: 0.000319), African in 5 of 24886 chromosomes (freq: 0.000201) and Latino in 7 of 35408 chromosomes (freq: 0.000198), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Ser390 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant also occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Oligodontia-cancer predisposition syndrome Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Apr 01, 2018	The AXIN2 variant designated as NM_004655.3:c.1168A>G (p.Ser390Gly) is classified as likely benign. This variant has been reported in several population databases. It is present in approximately 1 in 350 individuals with European ancestry (http://gnomad.broadinstitute.org/). This population frequency is much higher than other pathogenic variants in AXIN2 and not consistent with the reported oligodontia-cancer syndrome frequency. This variant has been reported as likely benign by other laboratories (ClinVar Variation ID: 127934). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter AXIN2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 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. -

Colorectal cancer;C4082304:Oligodontia Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 59 year old with a history of over 50 colon polyps. -

AXIN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2020

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	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	-0.043
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.29
Sift	Uncertain	0.022	D;.;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.17	.;B;B
Vest4		0.031
MVP		0.70
MPC		0.24
ClinPred		0.020	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.13

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: rs139871607; hg19: chr17-63534353; COSMIC: COSV104596686; COSMIC: COSV104596686;