rs35415678

Variant names:

• chr17-65536399-G-A
• rs35415678
• NM_004655.4:c.2062C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-65536399-G-A
• chr17-65536399-G-C
• chr17-65536399-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004655.4(AXIN2):​c.2062C>T​(p.Leu688Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0643 in 1,613,678 control chromosomes in the GnomAD database, including 6,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L688L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1473 hom., cov: 33)
  • Exomes 𝑓: 0.060 (4681 hom.)
• Consequence: AXIN2 NM_004655.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.31
• Publications: 25 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-65536399-G-A is Benign according to our data. Variant chr17-65536399-G-A is described in ClinVar as Benign. ClinVar VariationId is 259514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.2062C>T	p.Leu688Leu	synonymous_variant	Exon 8 of 11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.2062C>T	p.Leu688Leu	synonymous_variant	Exon 8 of 11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1867C>T	p.Leu623Leu	synonymous_variant	Exon 6 of 9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1867C>T	p.Leu623Leu	synonymous_variant	Exon 7 of 10	5		ENSP00000478916.1
AXIN2	ENST00000578251.1	n.284C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16801 AN: 152144 Hom.: 1455 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.0724

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0444

Gnomad OTH AF: 0.0927

GnomAD2 exomes AF: 0.0911 AC: 22294 AN: 244814 AF XY: 0.0834

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.0705

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0717

GnomAD4 exome AF: 0.0595 AC: 86973 AN: 1461416 Hom.: 4681 Cov.: 33 AF XY: 0.0584 AC XY: 42421 AN XY: 727004

African (AFR) AF: 0.220 AC: 7373 AN: 33478

American (AMR) AF: 0.157 AC: 7004 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 567 AN: 26124

East Asian (EAS) AF: 0.297 AC: 11793 AN: 39692

South Asian (SAS) AF: 0.0550 AC: 4743 AN: 86234

European-Finnish (FIN) AF: 0.0660 AC: 3503 AN: 53092

Middle Eastern (MID) AF: 0.0653 AC: 376 AN: 5756

European-Non Finnish (NFE) AF: 0.0429 AC: 47692 AN: 1111968

Other (OTH) AF: 0.0649 AC: 3922 AN: 60388

GnomAD4 genome AF: 0.111 AC: 16862 AN: 152262 Hom.: 1473 Cov.: 33 AF XY: 0.114 AC XY: 8505 AN XY: 74468

African (AFR) AF: 0.211 AC: 8771 AN: 41536

American (AMR) AF: 0.150 AC: 2300 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3470

East Asian (EAS) AF: 0.268 AC: 1381 AN: 5162

South Asian (SAS) AF: 0.0585 AC: 283 AN: 4834

European-Finnish (FIN) AF: 0.0724 AC: 769 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0444 AC: 3023 AN: 68022

Other (OTH) AF: 0.104 AC: 220 AN: 2114

Alfa AF: 0.0667 Hom.: 268

Bravo AF: 0.120

Asia WGS AF: 0.193 AC: 670 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0440

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oligodontia-cancer predisposition syndrome Benign:4

Jul 09, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Apr 28, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.2062C>T in AXIN2 gene is a synonymous change that involves a conserved nucleotide. 5/5 splice-site tools in Alamut predict this variant not to have an impact on normal splicing. The variant is present in the control population dataset of ExAC at an allele frequency of 9%. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.014%, suggesting that it is a benign polymorphism. Classification information about the variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16432638, 18790474) -

Hereditary cancer-predisposing syndrome Benign:2

Aug 19, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1,BP4,BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35415678; hg19: chr17-63532517; COSMIC: COSV61056020; COSMIC: COSV61056020;