Genetic Variant AXIN2:p.Pro600Ser (chr17-65536976-GGG-ACT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_004655.4(AXIN2):c.1798_1800delCCCinsAGT (p.Pro600Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P600?: Uncertain_significance (ClinVar VariationId 1390478, 1 star); p.P600A: Uncertain_significance (ClinVar VariationId 1780298, 1 star); p.P600H: Uncertain_significance (ClinVar VariationId 1780307, 1 star); p.P600L: Uncertain_significance (ClinVar VariationId 2067600, 2 stars); p.P600= (synonymous): Benign/Likely_benign (ClinVar VariationId 464572, 2 stars); p.P600= (synonymous): Likely_benign (ClinVar VariationId 3224377, 1 star); p.P600S: Uncertain_significance (ClinVar VariationId 464571, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

AXIN2
NM_004655.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.99

Publications

0 publications found

Variant links:

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 Submitted by: Ambry Genetics, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
craniosynostosis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

AXIN2 links:

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new If you want to explore the variant's impact on the transcript NM_004655.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 points.

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004655.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AXIN2	NM_004655.4	MANE Select	c.1798_1800delCCCinsAGT	p.Pro600Ser	missense	N/A	NP_004646.3	Q9Y2T1
	AXIN2	NM_001363813.1		c.1712+346_1712+348delCCCinsAGT		intron	N/A	NP_001350742.1	E7ES00

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AXIN2	ENST00000307078.10	TSL:1 MANE Select	c.1798_1800delCCCinsAGT	p.Pro600Ser	missense	N/A	ENSP00000302625.5	Q9Y2T1
AXIN2	ENST00000375702.5	TSL:1	c.1712+346_1712+348delCCCinsAGT		intron	N/A	ENSP00000364854.5	E7ES00
AXIN2	ENST00000881031.1		c.1798_1800delCCCinsAGT	p.Pro600Ser	missense	N/A	ENSP00000551090.1	Q9Y2T1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over