Variant classification summary

NM_004655.4:c.203G>A

AXIN2 · NP_004646.3:p.(Arg68Gln) · NM_004655.4

GRCh37: chr17:63554536 C>T · GRCh38: chr17:65558418 C>T

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

BP1 supporting BP4 moderate

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Arg68Gln)

gnomAD AF

0.00013120817739345584 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP1 (supporting) - AXIN2 germline disease is truncating-driven, so this missense change does not fit the established loss-of-function mechanism.

2

VUS: BP4 (moderate) - REVEL 0.176 for p.(Arg68Gln) sits at or below the 0.183 moderate benign threshold.

3

VUS: no Benign, Likely Benign, Pathogenic, or Likely Pathogenic combination is met by one supporting plus one moderate benign criterion with no pathogenic evidence.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion plus one moderate benign criterion does not satisfy the Benign (BA1 alone, or 2 strong benign) or Likely Benign (1 strong + 1 supporting, or 2 supporting benign) rules and no pathogenic combination is met, so the variant is classified Variant of Uncertain Significance.

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.203G>A in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Arg68Gln). 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: no report of the p.Arg68Gln amino-acid change established as pathogenic - the only record is ClinVar 127940, classified uncertain significance.	clinvar PMID:31285513 PMID:28944238 generic_acmg_combination_rules PMID:25741868
PS2	Not assessed	Not assessed: no proband or parental testing exists in any source, and the sole variant report (PMID:31285513) provides no parental genotype data.	PMID:25741868 PMID:31285513 clinvar
PS3	Not met	Not met: no functional assay exists for AXIN2 p.Arg68Gln - the only paper naming the variant (PMID:31285513) reports it as a class-3 VUS with zero functional testing.	clinvar oncokb PMID:31285513 pvs1_gene_context PMID:25741868
PS4	Not met	Not met: the only case observation is 1 carrier among 158 attenuated-polyposis patients, with no control group or odds ratio establishing enrichment.	clinvar PMID:31285513
PM1	Not met	Not met: CancerHotspots is negative at AXIN2 R68 and the variant itself sits in gnomAD at 0.013% with no homozygotes, so no hotspot or variation-free critical domain is established.	final_classification_framework PMID:31285513 gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
PM2	Not met	Not met: gnomAD AF 0.000131 (v4.1) and 0.000135 (v2.1), corroborated by a published European frequency of 2e-04, exceed the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:31285513
PM3	Not met	Not met: no pathogenic AXIN2 allele in trans, and 0 homozygotes among 37/274,598 gnomAD v2.1 alleles.	clinvar gnomad_v2 PMID:31285513 PMID:25741868
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.203G>A in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Arg68Gln). 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 missense change other than p.Arg68Gln is reported at codon 68, so the required pathogenic same-residue comparator does not exist.	pm5_candidates clinvar PMID:31285513 PMID:28944238 generic_acmg_combination_rules PMID:25741868
PM6	Not assessed	Not assessed: no parental testing or family data exist anywhere, and the sole variant report (PMID:31285513) documents no assumed de novo event.	PMID:25741868 PMID:31285513 clinvar
PP1	Not assessed	Not assessed: no pedigree or genotyped affected relative exists in any source, so zero informative co-segregation meioses can be counted for c.203G>A.	PMID:25741868 PMID:31285513 PMID:28944238 PMID:26467025 clinvar
PP2	Not met	Not met: AXIN2 disease is driven by truncating loss-of-function variants rather than missense, and no low benign-missense-rate constraint is established for the gene.	pvs1_gene_context oncokb generic_acmg_combination_rules PMID:25741868
PP3	Not met	Not met: REVEL 0.176 for p.(Arg68Gln) sits far below the >= 0.644 supporting PP3 threshold.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history is documented, and the only disease context (adenomatous polyposis) is genetically heterogeneous across APC, MUTYH and other genes.	PMID:31285513
PP5	Not met	Not met: ClinVar record 127940 has zero expert-panel submissions and no Pathogenic or Likely pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 AF 0.000131 and v2.1 AF 0.000135 are roughly two orders of magnitude below the 5% BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest gnomAD frequency, v4.1 grpmax FAF 0.000278, is ~36-fold below the 1% BS1 threshold.	gnomad_v2 gnomad_v4 PMID:31285513
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1 (37 alleles) and v4.1 (210 alleles), and AXIN2 disease is adult-onset with incomplete penetrance.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: no functional assay of AXIN2 p.Arg68Gln exists - the only protein-function statements are in-silico (ClinVar SCV000149781, SCV002584759), which cannot satisfy BS3.	clinvar oncokb PMID:31285513 pvs1_gene_context PMID:25741868
BS4	Not assessed	Not assessed: no family or non-segregation data exist in any source, and submitters' likely-benign classifications alone cannot establish BS4.	PMID:25741868 PMID:31285513 PMID:28944238 clinvar
BP1	Met	Met at supporting: AXIN2 disease is caused primarily by truncating loss-of-function variants, so this missense change qualifies for BP1 benign support.	pvs1_gene_context oncokb generic_acmg_combination_rules PMID:25741868
BP2	Not met	Not met: no pathogenic AXIN2 variant reported in cis or in trans with c.203G>A; the single carrier was heterozygous for this variant alone.	clinvar PMID:31285513 PMID:25741868
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.203G>A in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Arg68Gln). 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 (moderate): REVEL 0.176 for p.(Arg68Gln) is at or below the <= 0.183 moderate BP4 benign threshold.	revel clinvar generic_acmg_combination_rules
BP5	Not met	Not met: no affected individual carrying this variant has a documented alternate molecular basis for disease in any reviewed source.	PMID:31285513 clinvar
BP6	Not met	Not met: the two Likely benign ClinVar submissions for this variant are ordinary laboratory assertions, with zero expert-panel submissions on record.	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.203G>A in AXIN2 is a missense substitution predicted to produce NP_004646.3:p.(Arg68Gln). 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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