17-65536486-G-A

Position:

• chr17-65536486-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004655.4(AXIN2):​c.1975C>T​(p.Arg659Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000252 in 1,613,866 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00026 (4 hom.)
• Consequence: AXIN2 NM_004655.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.11

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 17-65536486-G-A is Benign according to our data. Variant chr17-65536486-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000261 (381/1461490) while in subpopulation MID AF= 0.0123 (71/5768). AF 95% confidence interval is 0.01. There are 4 homozygotes in gnomad4_exome. There are 227 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AXIN2	NM_004655.4	c.1975C>T	p.Arg659Trp	missense_variant	8/11	ENST00000307078.10	NP_004646.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AXIN2	ENST00000307078.10	c.1975C>T	p.Arg659Trp	missense_variant	8/11	1	NM_004655.4	ENSP00000302625.5
AXIN2	ENST00000375702.5	c.1780C>T	p.Arg594Trp	missense_variant	6/9	1		ENSP00000364854.5
AXIN2	ENST00000618960.4	c.1780C>T	p.Arg594Trp	missense_variant	7/10	5		ENSP00000478916.1
AXIN2	ENST00000578251.1	n.197C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000269 AC: 66 AN: 245028 Hom.: 0 AF XY: 0.000345 AC XY: 46 AN XY: 133168

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000261 AC: 381 AN: 1461490 Hom.: 4 Cov.: 33 AF XY: 0.000312 AC XY: 227 AN XY: 727032

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152376 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74522

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with non-syndromic tooth agenesis as well as individuals with a personal or family history including colorectal, sarcoma, and other cancers (Pedace 2011, Ballinger 2016, Raskin 2017, Haddaji Mastouri 2018); This variant is associated with the following publications: (PMID: 29114927, 28640387, 12101426, 21294210, 25236910, 15735151, 15538750, 15067328, 27498913, 29212164, 33193653) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2022	Variant summary: AXIN2 c.1975C>T (p.Arg659Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 245028 control chromosomes. The observed variant frequency is approximately 2 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 benign. c.1975C>T has been reported in the literature in at least one individual affected with Colorectal Cancer. These reports do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Oligodontia-cancer predisposition syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 03, 2019	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;C1837750:Oligodontia-cancer predisposition syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	.;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.62	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N;.;D
REVEL	Benign	0.22
Sift	Uncertain	0.025	D;.;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.32	.;B;B
Vest4		0.76
MVP		0.43
MPC		0.65
ClinPred		0.097	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.45

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: rs142670753; hg19: chr17-63532604; COSMIC: COSV61055585; COSMIC: COSV61055585;