rs2240308

Positions:

• chr17-65558473-G-A
• chr17-65558473-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004655.4(AXIN2):​c.148C>T​(p.Pro50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,605,836 control chromosomes in the GnomAD database, including 201,815 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (14296 hom., cov: 32)
  • Exomes 𝑓: 0.50 (187519 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7431378E-4).
• BP6: Variant 17-65558473-G-A is Benign according to our data. Variant chr17-65558473-G-A is described in ClinVar as [Benign]. Clinvar id is 259511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-65558473-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AXIN2	NM_004655.4	c.148C>T	p.Pro50Ser	missense_variant	2/11	ENST00000307078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AXIN2	ENST00000307078.10	c.148C>T	p.Pro50Ser	missense_variant	2/11	1	NM_004655.4	P1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60184 AN: 151988 Hom.: 14295 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.391

GnomAD3 exomes AF: 0.474 AC: 117123 AN: 247006 Hom.: 29707 AF XY: 0.479 AC XY: 63861 AN XY: 133402

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.325

Gnomad SAS exome AF: 0.469

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.502 AC: 729689 AN: 1453730 Hom.: 187519 Cov.: 79 AF XY: 0.500 AC XY: 361223 AN XY: 721970

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.514

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.396 AC: 60181 AN: 152106 Hom.: 14296 Cov.: 32 AF XY: 0.396 AC XY: 29414 AN XY: 74352

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.386

Alfa AF: 0.491 Hom.: 33055

Bravo AF: 0.385

TwinsUK AF: 0.520 AC: 1929

ALSPAC AF: 0.529 AC: 2040

ESP6500AA AF: 0.135 AC: 596

ESP6500EA AF: 0.528 AC: 4539

ExAC AF: 0.469 AC: 56987

Asia WGS AF: 0.366 AC: 1274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Oligodontia-cancer predisposition syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 25, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26514524, 29114927, 28204848, 27153395, 16820935, 19065536) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The c.148C>T variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 3/4 in-silico tools predict this variant to be benign. This variant is found in 56448/119156 control chromosomes (14394 homozygotes) from the large and broad populations of ExAC at a frequency of 0.4737319, which is about 3335 times greater than the maximal expected frequency of a pathogenic allele (0.0001421), suggesting this variant is a very common benign polymorphism. In a case-control study, authors found that the AXIN2 Pro50Ser SNP is associated with development of lung cancer as a protective SNP, while an association between the AXIN2 SNP and risk of colorectal cancer and of head and neck cancer was not observed (Kanzaki_IJMM_2006). Taken together, this variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2018

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.68
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.00017	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.00081	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N;.;.;N;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.37	T;.;.;T;.;.;.;T
Sift4G	Benign	0.57	T;T;T;T;.;.;.;.
Polyphen		0.0	.;.;B;B;.;.;.;.
Vest4		0.033
MPC		0.18
ClinPred		0.0076	T
GERP RS		2.8
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2240308; hg19: chr17-63554591; COSMIC: COSV61057354;