NM_004655.4:c.1168A>G

AXIN2 · NP_004646.3:p.(Ser390Gly) · NM_004655.4

GRCh37: chr17:63534353 T>C · GRCh38: chr17:65538235 T>C

Gene: AXIN2 Transcript: NM_004655.4

Final call

Likely Benign

BS2 strong BP1 supporting BP4 supporting

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Ser390Gly)

gnomAD AF

0.0010345746163710591 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BS2 strong: gnomAD v4.1 reports two homozygotes, subject to phenotype and penetrance review.

BP1 supporting: p.Ser390Gly is a missense variant in a loss-of-function AXIN2 disease mechanism.

BP4 supporting: REVEL 0.286 and SpliceAI max delta 0.004 meet the benign computational thresholds.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion plus one supporting benign criterion supports Likely Benign; BS2 strong with BP1 and BP4 supporting meets this rule.

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.1168A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ser390Gly). 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: the exact p.Ser390Gly variant was classified as a class 3 VUS, with no established pathogenic same-amino-acid substitution identified.	PMID:27300758 clinvar
PS2	Not assessed	Not assessed: parental genotypes and confirmed maternity/paternity are not reported for the exact variant in the available patient record.	PMID:27300758
PS3	Not assessed	Not assessed: the exact variant was reported clinically, but no variant-specific functional assay result or experimental readout was provided.	PMID:27300758
PS4	Not met	Not met: one reported case provides no case-control enrichment or statistically significant excess for the exact AXIN2 variant.	PMID:27300758 PMID:28944238
PM1	Not met	Not met: no approved AXIN2 domain entry covers Ser390, and hotspot review found no statistically significant hotspot at residue 390.	final_classification_framework
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 0.00103457, exceeding the generic PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no documented biallelic observation, pathogenic variant in trans, phase, or inheritance mode is available for AXIN2 c.1168A>G.	PMID:27300758
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.1168A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ser390Gly). 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 same-residue comparator was available, and the PM5 search artifact could not confirm complete classic PM5 semantics.	pm5_candidates PMID:27300758
PM6	Not assessed	Not assessed: no unconfirmed-parentage de novo observation is reported for the exact variant, and parental testing details are absent.	PMID:27300758
PP1	Not assessed	Not assessed: zero informative familial meioses or relative genotype-phenotype observations are reported for the exact variant.	PMID:27300758
PP2	Not met	Not met: AXIN2 disease mechanism is supported as loss of function, not as a gene with an established pathogenic-missense mechanism and rare benign missense variation.	pvs1_gene_context PMID:28944238
PP3	Not met	Not met: SpliceAI max delta 0.004 and REVEL 0.286 are below the PP3 supporting thresholds of 0.2 and 0.644, respectively.	spliceai revel bayesdel
PP4	Not met	Not met: colorectal cancer with MSH2/MSH6 loss and high microsatellite instability is not a phenotype highly specific for AXIN2.	PMID:27300758
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions and no exact-variant Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum population frequency is 0.00134658, far below the generic BA1 stand-alone threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 maximum population frequency is 0.00134658, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Met	Met: gnomAD v4.1 reports two homozygotes, although phenotype and penetrance information require human review before relying fully on BS2.	gnomad_v4
BS3	Not assessed	Not assessed: no validated assay demonstrated preserved AXIN2 function for the exact p.Ser390Gly variant.	PMID:27300758
BS4	Not assessed	Not assessed: no genotyped unaffected relatives or documented phenotype-discordant meioses are reported for the exact variant.	PMID:27300758
BP1	Met	Met, supporting: this is a missense p.Ser390Gly variant in AXIN2, whose established germline disease mechanism is supported as loss of function.	pvs1_gene_context
BP2	Not assessed	Not assessed: no documented cis or trans co-occurrence with a pathogenic variant is available for AXIN2 c.1168A>G.	PMID:27300758
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.1168A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ser390Gly). 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: REVEL 0.286 and SpliceAI max delta 0.004 both meet their supplied BP4 supporting thresholds of <=0.29 and <=0.1.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: MSH2/MSH6 loss is reported, but no confirmed alternate pathogenic molecular cause is identified to satisfy BP5.	PMID:27300758
BP6	Not met	Not met: ordinary ClinVar laboratory submissions cannot trigger BP6, and no exact-variant expert-panel Benign or Likely benign classification exists.	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.1168A>G in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Ser390Gly). 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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