Variant classification summary

NM_004655.4:c.2051C>T

AXIN2 · NP_004646.3:p.(Ala684Val) · NM_004655.4

GRCh37: chr17:63532528 G>A · GRCh38: chr17:65536410 G>A

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

PP4 supporting BP4 supporting

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Ala684Val)

gnomAD AF

0.0017059115131986616 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PP4 supporting: the exact variant occurred in a proband with isolated oligodontia and 10 missing teeth, an AXIN2-associated phenotype.

2

BP4 supporting: REVEL 0.157 meets the generic missense benign-effect threshold.

3

VUS: the applied supporting pathogenic and benign criteria conflict under the generic ACMG/AMP fallback.

Final determination: Under the generic ACMG/AMP fallback, conflicting supporting pathogenic and benign evidence (PP4 supporting and BP4 supporting) results in VUS because no specified pathogenic or benign combination is satisfied.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004655.4:c.2051C>T in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ala684Val). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: reviewed reports describe c.2051C>T p.Ala684Val itself, but no alternate nucleotide change producing the same amino-acid substitution was identified.	PMID:21626677 PMID:24581859 PMID:27696107
PS2	Not assessed	Not assessed: two reported probands are described, but neither publication documents parental testing confirming the variant was absent in both parents.	PMID:21626677 PMID:27696107
PS3	Not assessed	Not assessed: no reviewed publication reports a validated functional assay result for AXIN2 c.2051C>T (p.Ala684Val).	PMID:21626677 PMID:24581859 PMID:27696107
PS4	Not assessed	Not assessed: one oligodontia proband and 200 control chromosomes were reported, but no exact-variant case-control enrichment statistic was provided.	PMID:21626677 PMID:24581859 generic_acmg_combination_rules
PM1	Not assessed	Not assessed: no AXIN2 VCEP domain table or validated critical-domain evidence covers residue 684, and the hotspot search found no statistically significant hotspot.	oncokb
PM2	Not met	Not met: gnomAD v4.1 overall AF is 0.00170591, exceeding the PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: no applicable recessive AXIN2 framework is available, and the reports provide no affected-proband trans observation involving c.2051C>T.	PMID:21626677 PMID:27696107
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004655.4:c.2051C>T in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ala684Val). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no independently documented pathogenic or likely pathogenic alternate missense change at AXIN2 residue 684 was identified in the reviewed evidence.	PMID:21626677 PMID:24581859 PMID:27696107 clinvar
PM6	Not assessed	Not assessed: patient reports identify the variant, but neither publication states presumed de novo inheritance or supplies parental-genotype evidence.	PMID:21626677 PMID:27696107
PP1	Not assessed	Not assessed: reports identify individual patients, but provide no affected-relative genotypes, pedigree, or informative meioses demonstrating cosegregation.	PMID:21626677 PMID:24581859 PMID:27696107
PP2	Not assessed	Not assessed: available AXIN2 sources do not establish the required gene-wide pattern of common pathogenic and rare benign missense variation.	oncokb PMID:21626677 PMID:27696107
PP3	Not met	Not met: missense REVEL score 0.157 is below the PP3 supporting threshold of >=0.644.	revel
PP4	Met	Met supporting: the exact variant occurred in an AXIN2 proband with isolated oligodontia and 10 missing teeth, a phenotype associated with AXIN2.	PMID:21626677 PMID:27696107 generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant, and available assertions are non-expert submissions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum population AF is 0.00888994, below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 maximum population AF is 0.00888994, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: gnomAD v4.1 has six homozygotes, but their health status, age, and AXIN2 phenotype ascertainment are unavailable.	gnomad_v4 gnomad_v2 PMID:25741868
BS3	Not assessed	Not assessed: no reviewed publication reports a validated normal-function assay result for AXIN2 c.2051C>T (p.Ala684Val).	PMID:21626677 PMID:24581859 PMID:27696107
BS4	Not assessed	Not assessed: no clinically informative unaffected relatives with variant-positive testing or pedigree-level non-segregation are reported.	PMID:21626677 PMID:27696107
BP1	Not assessed	Not assessed: truncating-versus-missense AXIN2 evidence is suggestive but not a validated gene-specific mechanism sufficient for BP1.	oncokb PMID:27696107
BP2	Not assessed	Not assessed: no report documents c.2051C>T in cis with a pathogenic variant or in trans with another pathogenic variant in an affected individual.	PMID:21626677 PMID:27696107
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004655.4:c.2051C>T in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ala684Val). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: missense REVEL score 0.157 meets the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no documented alternate pathogenic variant explains a relevant phenotype in an individual carrying c.2051C>T.	generic_acmg_combination_rules
BP6	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant, so non-expert Benign and Likely benign labels cannot trigger BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004655.4:c.2051C>T in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ala684Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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