AXIN2 c.148C>T, p.Pro50Ser
NM_004655.4:c.148C>T
COSMIC ID: COSM4000258
Likely Benign
The variant P50S in AXIN2 is extremely common in population databases (gnomAD MAF 46.6%), with computational and database evidence supporting no impact on function. BA1 stand-alone criterion applies, leading to a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BP1
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
AXIN2
Transcript
NM_004655.4
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004655.3 | Alternative | 11 exons | Reverse |
| NM_004655.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_004655.4:c.148C>T
Protein Change
P50S
Location
Exon 2
(Exon 2 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 50 in gene AXIN2
Alternate Identifiers
COSM4000258
Variant interpretation based on transcript NM_004655.4
Genome Browser
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HGVS InputNM_004655:c.148C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
46.6%
Common
Highest in Population
Admixed American
54.7%
Common
Global: 46.6%
Admixed American: 54.7%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 278326Alt: 129827Homozygotes: 32761
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 46.6%, 129827/278326 alleles, homozygotes = 32761) and at a higher frequency in the Admixed American population (MAF= 54.7%, 19194/35080 alleles, homozygotes = 5345). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
1 publications
Benign
Based on 15 submitter reviews in ClinVar
Submitter Breakdown
15 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
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.
Clinical Statement
This variant has been reported in ClinVar as Benign (15 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 50 in gene AXIN2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.126
0.126
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.17polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene). The evidence for this variant shows: it is a missense variant (P50S) and not a null variant. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: Same amino acid change as a known pathogenic variant but different nucleotide change. The evidence for this variant shows: no known pathogenic variant causes the same P50S amino acid change. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: Well-established functional studies supportive of a damaging effect on the gene or gene product. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because there is no damaging functional evidence.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: Prevalence in affected individuals significantly increased compared with controls. The evidence for this variant shows: no case-control or affected individual data are available. Therefore, this criterion is not applied due to lack of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: Located in a mutational hot spot or well-established functional domain without benign variation. The evidence for this variant shows: P50 is not within a recognized hotspot or critical functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM2 is: Absent from controls (or at extremely low frequency if recessive). The evidence for this variant shows: gnomAD allele frequency is 46.6%, which is common. Therefore, this criterion is not applied because the variant is not absent or rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: Detected in trans with a pathogenic variant (for recessive disorders). The evidence for this variant shows: no trans observations with a pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: Protein length changes due to in-frame deletions/insertions or stop-loss variants. The evidence for this variant shows: it is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: Novel missense change at an amino acid residue where a different pathogenic missense change has been seen. The evidence for this variant shows: no other pathogenic missense changes have been reported at residue P50. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: Assumed de novo, but without confirmation of paternity and maternity. The evidence for this variant shows: no assumed de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: Co-segregation with disease in multiple affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. The evidence for this variant shows: AXIN2 disease mechanism is loss of function and missense variants are not a primary known mechanism. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact). The evidence for this variant shows: computational evidence (REVEL=0.13, CADD/PolyPhen benign, SpliceAI=0.04) predicts no deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: Patient's phenotype or family history highly specific for a disease with a single genetic etiology. The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: Reputable source reports variant as pathogenic, but without accessible evidence. The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: Allele frequency is too high for the disorder (based on population data). The evidence for this variant shows: gnomAD allele frequency of 46.6% with 32,761 homozygotes. Therefore, this criterion is applied at Stand-alone because the allele frequency far exceeds any threshold for pathogenicity.
BS1
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: Allele frequency is greater than expected for the disorder. The evidence for this variant shows: gnomAD MAF of 46.6%, which is orders of magnitude above the maximum credible frequency. Therefore, this criterion is applied at Strong because the frequency is well above expectations for a pathogenic variant.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: Observed in healthy individuals with full penetrance expected at an early age. The evidence for this variant shows: no specific data on healthy individuals with phenotype. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: Well-established functional studies show no damaging effect on protein function or splicing. The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: Lack of segregation in affected family members. The evidence for this variant shows: no segregation analysis available. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: Missense variant in a gene where only LoF causes disease. The evidence for this variant shows: AXIN2 disease mechanism is loss of function and P50S is a missense change. Therefore, this criterion is applied at Supporting because missense variants in this gene are unlikely to be pathogenic.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant. The evidence for this variant shows: no data on cis/trans with a pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: In-frame deletions/insertions in a repetitive region without known function. The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). The evidence for this variant shows: REVEL score 0.13, benign CADD/PolyPhen predictions, SpliceAI 0.04. Therefore, this criterion is applied at Supporting because computational data support a benign impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: Variant found in a case with an alternate molecular basis for disease. The evidence for this variant shows: no case data with alternate molecular basis. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: Reputable source reports variant as benign, but without accessible evidence. The evidence for this variant shows: ClinVar lists it as Benign by 15 laboratories without underlying data. Therefore, this criterion is applied at Supporting because a reputable source reports it as benign.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: Synonymous variant with no predicted impact on splicing. The evidence for this variant shows: it is a missense variant, not synonymous. Therefore, this criterion is not applied.