Variant classification summary

NM_004655.4:c.1985T>C

AXIN2 · NP_004646.3:p.(Leu662Pro) · NM_004655.4

GRCh37: chr17:63532594 A>G · GRCh38: chr17:65536476 A>G

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

BP4 moderate

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Leu662Pro)

gnomAD AF

0.0012045176848476137 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 moderate: REVEL 0.169 supports a computationally benign effect below the 0.183 moderate threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, BP4 moderate alone does not meet the threshold for Likely Benign or Benign, so the final call is VUS.

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.1985T>C in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Leu662Pro). 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 assessed	Not assessed: no validated pathogenic or likely pathogenic comparator producing the same p.Leu662Pro amino-acid change was identified.	clinvar
PS2	Not assessed	Not assessed: no proband-level parental genotypes or validated maternity and paternity are documented for this variant.
PS3	Not assessed	Not assessed: no variant-specific functional assay result or validated assay control is documented for AXIN2 p.Leu662Pro.
PS4	Not assessed	Not assessed: no affected-case/control counts, enrichment statistic, or exact-variant prevalence is available for PS4.	PMID:25394175 PMID:29641532 PMID:38136308 clinvar
PM1	Not assessed	Not assessed: AXIN2 residue 662 has no authoritative critical-domain evidence and the hotspot resource reports no statistically significant hotspot.	oncokb
PM2	Not met	Not met: gnomAD v4.1 overall AF is 0.00120452, exceeding the generic PM2 threshold of <=0.0001.	gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: available AXIN2 disease reports describe heterozygous familial disease, not the recessive biallelic model required for PM3.
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.1985T>C in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Leu662Pro). 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 assessed	Not assessed: no established pathogenic or likely pathogenic alternate missense change at AXIN2 Leu662 was available.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no clinical report documents an apparently de novo occurrence without parental testing for this variant.
PP1	Not assessed	Not assessed: no informative affected-relative genotypes, meioses, pedigree, or phenotype-segregation data are documented.
PP2	Not assessed	Not assessed: available AXIN2 context does not establish a high pathogenic missense rate with low benign missense variation.	oncokb
PP3	Not met	Not met: REVEL 0.169 is below the 0.644 supporting PP3 threshold.	revel
PP4	Not assessed	Not assessed: no patient phenotype, family history, or highly specific AXIN2-related clinical presentation is documented for the exact variant.	clinvar
PP5	Not assessed	Not assessed: exact-variant ClinVar record 127939 has 0 expert-panel submissions and no qualifying Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 0.00438596, below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest observed allele frequency is 0.00438596, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 5 homozygotes in v4.1, but their health, age, phenotype status, and AXIN2 disease penetrance are not established.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific functional assay result or validated assay control is documented showing normal AXIN2 p.Leu662Pro function.
BS4	Not assessed	Not assessed: no informative affected relatives, unaffected relatives, or paired genotype-phenotype observations permit non-segregation analysis.
BP1	Not assessed	Not assessed: AXIN2 truncating variants are mentioned, but a primarily truncating disease mechanism is not established.	oncokb
BP2	Not assessed	Not assessed: no affected-proband co-occurrence, second pathogenic allele, or phase information is available for c.1985T>C.
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.1985T>C in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Leu662Pro). 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 at moderate strength: REVEL 0.169 is below the 0.183 moderate BP4 threshold.	revel
BP5	Not assessed	Not assessed: no documented alternative molecular cause explains the relevant phenotype, so BP5 cannot be applied.	clinvar
BP6	Not assessed	Not assessed: exact-variant ClinVar record 127939 has 0 expert-panel submissions and no qualifying Benign or Likely benign expert-panel classification.	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.1985T>C in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Leu662Pro). 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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