17-65534032-C-T

Position:

• chr17-65534032-C-T

Variant summary

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

The NM_004655.4(AXIN2):​c.2285G>A​(p.Ser762Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000613 in 1,614,260 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).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 0.507

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=0.016982198).
• BP6: Variant 17-65534032-C-T is Benign according to our data. Variant chr17-65534032-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127944.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=2}. Variant chr17-65534032-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.2285G>A	p.Ser762Asn	missense_variant	10/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.2285G>A	p.Ser762Asn	missense_variant	10/11	1	NM_004655.4	ENSP00000302625	P1
AXIN2	ENST00000375702.5	c.2090G>A	p.Ser697Asn	missense_variant	8/9	1		ENSP00000364854
AXIN2	ENST00000618960.4	c.2090G>A	p.Ser697Asn	missense_variant	9/10	5		ENSP00000478916
AXIN2	ENST00000578251.1	n.507G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000896

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251492 Hom.: 1 AF XY: 0.000765 AC XY: 104 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000614 AC: 897 AN: 1461886 Hom.: 2 Cov.: 33 AF XY: 0.000594 AC XY: 432 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000647

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74512

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000927 Hom.: 2

Bravo AF: 0.000725

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00125

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2020	The AXIN2 c.2285G>A; p.Ser762Asn variant (rs117688560), to our knowledge, is not reported as a germline variant in an individual with hereditary cancer, but has been reported as a somatic variant in a hepatoblastoma (Mazzoni 2014). The variant is reported in the ClinVar database (Variation ID: 127944) and is found in the general population with an overall allele frequency of 0.07% (196/282,902 alleles, including 1 homozygote) in the Genome Aggregation Database. The serine at codon 762 is moderately conserved and computational analyses predict that this variant is neutral (REVEL 0.065). Due to limited information, the clinical significance of the p.Ser762Asn variant is uncertain at this time. While the population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Ser762Asn variant is uncertain at this time. References: Mazzoni SM and Fearon ER. AXIN1 and AXIN2 variants in gastrointestinal cancers. Cancer Lett. 2014 Dec 1;355(1):1-8. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	This variant is associated with the following publications: (PMID: 24631698, 25236910, 15841489, 29114927) -

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2022	- -

Oligodontia-cancer predisposition syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2022	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. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

AXIN2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2019

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	0.095
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	.;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.71	.;T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.58	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.27	N;.;N
REVEL	Benign	0.065
Sift	Benign	0.36	T;.;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.32
MVP		0.49
MPC		0.28
ClinPred		0.016	T
GERP RS		4.7
gMVP		0.15

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: rs117688560; hg19: chr17-63530150; COSMIC: COSV61056885; COSMIC: COSV61056885;