Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About AXIN2
AXIN2 is a scaffolding protein that helps regulate the Wnt signaling pathway, a key developmental pathway controlling cell growth and fate. It is part of the beta-catenin destruction complex, where it helps mark beta-catenin for degradation when Wnt signaling is off, and it also assists in relaying Wnt signals to the nucleus when the pathway is active. AXIN2 acts as a tumor suppressor, and mutations in the gene have been linked to colorectal cancer as well as familial tooth agenesis with predisposition to colorectal cancer. Its expression has also been associated with prostate cancer recurrence.
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01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP1Supporting
BP1 · supporting
Met at supporting: AXIN2 disease is caused primarily by truncating loss-of-function variants, so this missense change qualifies for BP1 benign support.
BP4Moderate
BP4 · moderate
Met (moderate): REVEL 0.176 for p.(Arg68Gln) is at or below the <= 0.183 moderate BP4 benign threshold.
Recorded classification: Uncertain significance
VUS: BP1 (supporting) and BP4 (moderate) are the only met criteria, and together they fall short of the generic ACMG/AMP Likely Benign combination.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
210 / 1,600,510 alleles
gnomAD v4.1: 210 / 1,600,510 alleles. Recorded AF 0.000131208. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000134742; MAF= 0.01347%, 37/274598 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000257658; MAF= 0.02577%, 9/34930 alleles, homozygotes = 0); grpmax FAF= 0.00015724.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AXIN2, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 17 not met · 5 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All four segregation/de novo criteria (PS2, PM6, PP1, BS4) are unassessable in this case because no proband-level, parental, pedigree, or meiosis data exist for AXIN2 c.203G>A in the case record, the ClinVar record (ClinVarID 127940), or any reviewed publication. PS2 and PM6 fail their minimum observation requirement (no parental testing or parental status, and no de novo statement for the one reported occurrence in PMID:31285513, patient ID 79), while PP1 and BS4 fail theirs (no pedigree, no genotyped relatives, no informative meioses, hence no co-segregation or non-segregation can be counted). Absence of these data is a gap, not evidence against pathogenicity: each criterion is recorded as not_assessed rather than not_met, and none contributes evidence points.
Governing framework: no ClinGen CSPEC is available for AXIN2 and no gene-specific VCEP specification exists (framework_complete=false), so generic ACMG/AMP 2015 criteria and combination rules apply. ClinVar submitter classifications (6 uncertain significance, 2 likely benign) and gnomAD frequency data were not used to satisfy any criterion in this group, in line with the rule that no criterion may be inferred from another source's final classification.
Governing framework is generic ACMG/AMP 2015 (Richards et al., PMID:25741868): no ClinGen CSPEC and no gene-specific VCEP exists for AXIN2, and no local index guidance was supplied, so PS3/BS3 are applied with their published generic definitions.
Neither PS3 nor BS3 is met: no functional assay of any kind has been performed on AXIN2 c.203G>A p.(Arg68Gln). The functional claims attached to this variant in ClinVar and OncoKB are in-silico predictions with the absence of functional confirmation explicitly noted by one submitter.
Gene-level AXIN2 Wnt/beta-catenin functional assay systems have been validated for other variants (PMID:41361419, PMID:23838596), so this VUS is experimentally resolvable, but no assay result at codon 68 exists in the reviewed evidence base; re-adjudication is indicated if such a study is published.
PP5 and BP6 both fail on the expert-panel gate: the exact-variant ClinVar record 127940 has zero expert-panel submissions. Its 9 submissions are 6 Uncertain significance and 2 Likely benign ordinary-laboratory assertions, so neither PP5 (no P/LP expert-panel call) nor BP6 (no B/LB expert-panel call) is met.
PS4 is not met: the only case observation of AXIN2 c.203G>A is a single heterozygous carrier among 158 attenuated adenomatous polyposis patients (PMID:31285513, patient ID 79), with no control group, odds ratio or enrichment analysis anywhere in the source.
PP4 is not assessed: no proband phenotype, clinical indication or family history is documented for this case, and the only disease context (attenuated adenomatous polyposis) is genetically heterogeneous across APC, MUTYH, POLE, POLD1, NTHL1, MSH3 and AXIN2.
BP5 is not met: no carrier of this variant is reported with an alternate molecular basis for disease; patient ID 79 has no co-occurring pathogenic APC/MUTYH variant.
No AXIN2 ClinGen CSPEC or VCEP specification exists for this case (framework_mode = generic_acmg, cspec found = false), so generic ACMG/AMP 2015 criteria were applied; consequently no gene-specific numeric threshold, and no >=/<= operator comparison, applies to any criterion in this group.
Neither allelic criterion is met: NM_004655.4:c.203G>A has never been reported in cis or in trans with a pathogenic AXIN2 variant, and no biallelic (homozygous or compound heterozygous) occurrence is documented.
The only affected carrier reported in the literature (patient ID 79, PMID:31285513) was heterozygous for this class-3 (uncertain significance) variant alone, in a cohort in which all validated variants were heterozygous; gnomAD v2.1 records 0 homozygotes among 37/274,598 alleles.
PM3's recessive premise is also unmet: AXIN2 disease is reported in heterozygous carriers, with no AXIN2-associated recessive disorder documented in the retrieved evidence.
No ClinGen CSPEC/VCEP or local gene framework exists for AXIN2 (framework_mode = generic_acmg), so generic ACMG/AMP 2015 definitions of PM3 and BP2 (PMID:25741868) were applied.
PP3/BP4 are computational-evidence criteria scoped by the variant's own consequence: NM_004655.4:c.203G>A is a missense substitution (NP_004646.3:p.(Arg68Gln)), so exactly one path applies - REVEL - and the SpliceAI splice path was not used for either criterion, even though a SpliceAI record (scoreless, query timeout) exists in the evidence set.
REVEL v1.3 score = 0.176. Against the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997): below the PP3 supporting cutoff of 0.644 -> PP3 not met; at or below the BP4 moderate cutoff of 0.183 and the BP4 supporting cutoff of 0.29 -> BP4 met at moderate strength.
BayesDel (-0.262489) was deliberately not used: no generic ACMG-strength calibration is established for it, so it is not_available for PP3/BP4 here.
No ClinGen CSPEC specification and no VCEP/gene-specific framework exists for AXIN2 (generic ACMG/AMP 2015 fallback), so no gene-specific pre-assigned PP3/BP4 code was available to apply and the published generic thresholds govern.
The REVEL-based BP4 direction is concordant with two independent clinical-laboratory ClinVar submissions on this exact variant (St. Jude SCV002584759; GeneDx SCV000149781), each reporting a benign in silico prediction for the same variant.
Population criteria group (BA1, BS1, BS2, PM2) assessed for AXIN2 NM_004655.4:c.203G>A (p.(Arg68Gln), rs138056036), a rare missense variant reported in ClinVar (variation 127940) with conflicting interpretations.
No gene-specific framework governs this case: ClinGen CSPEC was not found (cspec found=false), no AXIN2 VCEP materials or local gene framework are present, and the case declares framework_mode = generic_acmg with final_classification_framework source = generic_acmg_fallback. Generic ACMG/AMP 2015 criteria and the supplied generic population-frequency thresholds therefore apply.
All four population criteria are not met. The variant is rare but established at a low frequency: gnomAD v2.1 total AF 0.000134742 and gnomAD v4.1 total AF 0.000131208, with a top ancestry frequency of 0.000404 (Admixed American, v4.1) and grpmax FAF up to 0.000278 (v4.1).
BA1 (>= 0.05) and BS1 (>= 0.01) are far from satisfied: the highest frequency observed anywhere, including the most frequent ancestry and the grpmax FAF, is ~25- to 36-fold below the 1% BS1 threshold and two orders of magnitude below the 5% BA1 threshold.
BS2 is not met: gnomAD reports zero homozygotes for this variant in both v2.1 (37 alleles) and v4.1 (210 alleles), and the AXIN2-associated disorder is adult-onset with incomplete penetrance, so no healthy-adult observation supports it.
PM2 supporting (<= 0.0001) is not met: the all-comers gnomAD AF (~1.3e-4) and the published European (non-Finnish) frequency of 2e-04 (PMID:31285513) both exceed the 1e-4 threshold, by a margin of about 1.3-fold on the most conservative (v4.1 exome) value.
Overall this group supplies no benign-direction frequency evidence strong enough to reach BA1/BS1 and no PM2 supporting evidence; the variant's population rarity is insufficient for PM2 under the generic 1e-4 threshold but is also well below any BS1/BA1 frequency.
No criteria match.
Met · 2
BP1SupportingMet at supporting: AXIN2 disease is caused primarily by truncating loss-of-function variants, so this missense change qualifies for BP1 benign support.
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Reasoning
BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease (Richards et al. 2015, PMID:25741868). AXIN2's germline disease mechanism is predominantly truncating loss of function: pvs1_gene_context records lof_mechanism_supported=true, its supporting literature set was assembled from loss-of-function/truncating queries, and OncoKB's curated gene entry states that truncating AXIN2 mutations are those associated with colorectal cancer in a gene described as a tumor suppressor. This variant is a missense substitution (NP_004646.3:p.(Arg68Gln), c.203G>A) rather than a truncating allele, so it falls within the class BP1 was written for, and it is applied at the default supporting strength. Flagged for human review and caveated because occasional functionally supported missense AXIN2 variants have been reported; if missense pathogenicity in AXIN2 were to become well established, BP1's 'primarily truncating' premise would need re-examination.
Rule
ACMG/AMP 2015 BP1 (missense variant in a gene for which primarily truncating variants are known to cause disease) - PMID:25741868
Evidence considered
pvs1_gene_context: lof_mechanism_supported=true for AXIN2 germline disease; literature queries included 'AXIN2 truncating variant germline' and 'AXIN2 inherited disease loss of function'.
OncoKB gene curation: AXIN2 is a tumor suppressor; 'Truncating mutations in AXIN2 have been associated with colorectal cancer'.
Gene summary: AXIN2 acts as a tumor suppressor in the Wnt/beta-catenin destruction complex, with mutations linked to colorectal cancer and to familial tooth agenesis with predisposition to colorectal cancer.
Variant class: NC_000017.10:g.63554536C>T / NM_004655.4:c.203G>A encodes the missense substitution NP_004646.3:p.(Arg68Gln), not a truncating allele.
Caveat recorded for review: occasional missense AXIN2 variants with functional support are reported (PMID:23838596 in attenuated FAP with LOH and segregation data; PMID:41361419 p.Thr693Met with aberrant Wnt/beta-catenin activation), which could weaken BP1's 'primarily truncating' premise if replicated.
Still missing
Rare missense AXIN2 variants with functional support have been reported (PMID:23838596 attenuated FAP family with LOH/segregation data; PMID:41361419 tooth agenesis p.Thr693Met with in vitro Wnt activation), so BP1 should be re-reviewed if missense pathogenicity in AXIN2 becomes well established.
No formal gene-specific missense/LoF mechanism specification exists for AXIN2; this determination rests on the generic ACMG definition plus the curated gene-level literature in this case.
BP4ModerateMet (moderate): REVEL 0.176 for p.(Arg68Gln) is at or below the <= 0.183 moderate BP4 benign threshold.
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Reasoning
BP4 applies to computational evidence suggesting no impact on gene or gene product. NM_004655.4:c.203G>A is a missense substitution (NP_004646.3:p.(Arg68Gln)), so BP4 is taken from the missense protein-impact path, REVEL, and only from that path; the SpliceAI splice path is not applicable to a missense variant and no splice prediction was used, either for or against this criterion. The calibrated REVEL score for this allele (chr17:g.65558418C>T, GRCh38) is 0.176, which satisfies the ClinGen SVI REVEL BP4 moderate cutoff of <= 0.183 and the supporting cutoff of <= 0.29, but not the strong cutoff of <= 0.016 (Pejaver et al. 2022, PMID:36413997). The score clears the moderate cutoff narrowly (0.176 vs 0.183, a margin of 0.007) while clearing the supporting cutoff comfortably, so BP4 is met at moderate strength; the direction of the evidence (benign effect on protein function) is secure either way. Independent clinical-laboratory ClinVar submissions on this exact variant reach the same in silico conclusion for the same tool: St. Jude Molecular Pathology (SCV002584759) states that 'the in silico tool revel predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies', and GeneDx (SCV000149781) states that 'in silico analysis indicates that this missense variant does not alter protein structure/function'. The local BayesDel score (-0.262489) is excluded from this assessment because no generic ACMG-strength BayesDel calibration exists, and it is not needed here. No ClinGen CSPEC specification and no VCEP/gene-specific framework exists for AXIN2 (framework_complete = false), so the generic ACMG/AMP 2015 BP4 criterion with the published REVEL calibration applies. BP4 is met, strength moderate.
Rule
missense -> REVEL path; BP4 met at moderate because REVEL 0.176 <= 0.183 (and <= 0.29 supporting), but > 0.016 strong (Pejaver et al. 2022, PMID:36413997)
Evidence considered
Consequence class: missense (NP_004646.3:p.(Arg68Gln)) - BP4 taken from the REVEL missense path only, not from SpliceAI; the two paths are never combined and no prediction is double-counted.
REVEL v1.3 local lookup (revel block): score 0.176 for chr17:g.65558418C>T (GRCh38), the same allele as NC_000017.10:g.63554536C>T.
Thresholds applied: BP4 supporting requires REVEL <= 0.29; moderate <= 0.183; strong <= 0.016 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, Am J Hum Genet, PMID:36413997). 0.176 meets supporting and moderate but not strong.
Concordant ClinVar submitter in silico statements for the exact variant: SCV002584759 (St. Jude Molecular Pathology) - REVEL predicts a benign effect on protein function; SCV000149781 (GeneDx) - in silico analysis indicates this missense variant does not alter protein structure/function.
BayesDel (-0.262489) excluded: no generic ACMG-strength calibration is established, so it is treated as not_available for PP3/BP4 rather than as an additional benign predictor.
SpliceAI returned no score for this variant (query timeout; max_delta_score null, Pangolin SG 0.067/SL -0.008 only) and the uncalibrated Pangolin output was not used; being a missense variant, the splice path is out of scope for BP4 here.
No ClinGen CSPEC record and no VCEP/gene-specific PP3-BP4 lookup material exists for AXIN2, so no gene-specific pre-assigned code overrides the generic thresholds.
Still missing
The REVEL score (0.176) clears the moderate BP4 cutoff (<= 0.183) by only 0.007, so the moderate-vs-supporting strength grade is borderline; the criterion itself is met at no less than supporting strength.
PS1Not met: no report of the p.Arg68Gln amino-acid change established as pathogenic - the only record is ClinVar 127940, classified uncertain significance.
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Reasoning
PS1 requires that the same amino-acid change (p.Arg68Gln) has previously been established as pathogenic (Richards et al. 2015, PMID:25741868). The only report of p.Arg68Gln anywhere in this case is the variant itself: ClinVar variation 127940 (NM_004655.4(AXIN2):c.203G>A, p.Arg68Gln), whose submissions are uncertain significance or likely benign with no expert-panel review and no assertion of pathogenicity, and the attenuated adenomatous polyposis cohort of PMID:31285513, where it is listed as class 3 (variant of uncertain significance). No distinct nucleotide change encoding p.Arg68Gln and no other p.Arg68Gln record classified pathogenic or likely pathogenic was found in ClinVar or in the fetched papers (PMID:28944238, PMID:27153395, PMID:26467025). The prerequisite of PS1 therefore fails.
Rule
ACMG/AMP 2015 PS1 (same amino-acid change as a previously established pathogenic variant) - PMID:25741868
Evidence considered
ClinVar variation 127940 (NM_004655.4(AXIN2):c.203G>A, p.Arg68Gln): 9 submissions, 6 uncertain significance and 2 likely benign, no expert-panel review, no submission asserting a pathogenic role for the amino-acid change.
PMID:31285513 Table 2 lists c.203G>A p.(Arg68Gln) (rs138056036) as class 3 (uncertain significance) in a 158-patient attenuated adenomatous polyposis cohort; the paper reports no other codon-68 variant and no actionable AXIN2 variant.
Searched the fetched full texts for any established pathogenic variant encoding p.Arg68Gln: PMID:28944238 names only the AXIN2 in-frame indel p.His474_Ser475insHis; PMID:27153395 names neither AXIN2 nor the variant; PMID:26467025 discusses known pathogenic variants at the same residue as an evidence type but includes no AXIN2 variant.
Still missing
No exhaustive ClinVar/gnomAD sweep for a second nucleotide substitution encoding p.Arg68Gln was performed; none is reported in any source consulted here.
PS3Not 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.
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Reasoning
PS3 requires well-established functional assay evidence that the variant has a deleterious effect on protein or gene function. No such assay exists for AXIN2 NM_004655.4:c.203G>A p.(Arg68Gln) (NP_004646.3:p.Arg68Gln). The only peer-reviewed report naming this exact variant (Lorca et al., PMID:31285513, Table 2) detected it in a single attenuated adenomatous polyposis patient by multigene panel sequencing and classified it as class 3 (ACMG-SHERLOC VUS); that paper performed no functional, biochemical, splicing, or reporter assay on it. OncoKB returned 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. The ClinVar record (VCV000127940) contains no functional-assay submission: one submitter (St. Jude, SCV002584759) states that the benign in-silico prediction 'has not been confirmed by functional studies', and the other function-related submission (GeneDx, SCV000149781) is explicitly in-silico ('in silico analysis indicates that this missense variant does not alter protein structure/function'). The remaining screened publications (PMID:28944238, PMID:27153395, PMID:26467025, PMID:25394175) do not name AXIN2 or this variant and performed no assay on it. Gene-level AXIN2 assay work present in the case artifacts (pvs1_gene_context; e.g. PMID:41361419) applied Wnt/beta-catenin in-vitro reporter and patient-PBMC mRNA assays only to c.2078C>T (p.Thr693Met) and c.1060-3T>C, and PMID:23838596 characterized a different AXIN2 missense variant without a pathway assay - none of it addresses codon 68. A single somatic occurrence in COSMIC (COSV100196332) is an observation count, not a functional assay. PS3 is therefore not met: there is no functional-assay evidence, positive or negative, for this variant. No ClinGen CSPEC/VCEP specification exists for AXIN2 (case_summary.cspec.found = false; vcep_materials.final_classification_framework.found = false), so the generic ACMG/AMP 2015 PS3 definition (PMID:25741868) governs.
Rule
PS3 (generic ACMG/AMP 2015, PMID:25741868): well-established functional studies show a deleterious effect. Applies only to a validated assay performed on the variant in question; no AXIN2-specific VCEP/CSPEC calibration exists, so no strength modification is available.
Evidence considered
ClinVar record for variation 127940 (submitter St. Jude Molecular Pathology, SCV002584759) states of the AXIN2 c.203G>A variant: 'the in silico tool revel predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies' - indicating no functional assay has been performed on this variant.
ClinVar submitter GeneDx (SCV000149781) records only a computational statement: 'in silico analysis indicates that this missense variant does not alter protein structure/function'. This is an in-silico prediction, not a functional assay, and cannot be used as PS3 (or BS3) evidence.
OncoKB gene page for AXIN2 R68Q reports classification 'Unknown Oncogenic Effect' and states that no variant-specific reviewed functional evidence was identified for this variant; only gene-level WNT-pathway tumour-suppressor context is provided.
Lorca et al. 2019 (PMID:31285513, Table 2, patient ID 79) is the only reviewed publication listing c.203G > A p.(Arg68Gln) rs138056036; it was detected in 1 of 158 attenuated adenomatous polyposis patients by a multigene NGS panel and classified as class 3 (ACMG-SHERLOC VUS, AXIN1_TNKS domain). The paper presents no functional, segregation, or somatic data specific to this variant.
COSMIC records one somatic occurrence of this variant (COSV100196332, n = 1); a single somatic observation is not a functional assay and does not support PS3.
Gene-level AXIN2 assay literature held in the case artifacts (pvs1_gene_context, supporting papers PMID:41361419 and PMID:23838596): the in-vitro functional work (Wnt/beta-catenin activation assay, PBMC mRNA quantification) targeted other AXIN2 variants - c.2078C>T p.(Thr693Met) and c.1060-3T>C - while PMID:23838596 argued pathogenicity for a different AXIN2 missense variant without a pathway assay. No functional result exists at codon 68.
Searched all screened publications and database sources for variant-specific functional evidence using the identifiers 'c.203G>A', 'c.203G > A', 'p.(Arg68Gln)', 'p.R68Q', 'R68Q' and 'rs138056036'; no reporter, minigene, protein-function, mRNA or other assay result was returned for this variant.
Governing framework: no ClinGen CSPEC or gene-specific VCEP was found for AXIN2 (case_summary.cspec.found = false; vcep_materials.final_classification_framework.source = 'generic_acmg_fallback'), and no index guidance was present, so the generic ACMG/AMP 2015 criteria as published by Richards et al. (PMID:25741868) are applied unchanged.
Still missing
No functional assay (e.g. Wnt/beta-catenin reporter, AXIN2 protein-stability or degradation assay, minigene/RNA assay) has been performed on AXIN2 p.Arg68Gln in any source reviewed; PS3 cannot be met without one, and its absence is the reason for the not_met verdict rather than a negative assay result.
AXIN2 has no ClinGen CSPEC/VCEP specification, so there is no VCEP-defined assay (or strength-calibration rule) available as a substitute.
PS4Not met: the only case observation is 1 carrier among 158 attenuated-polyposis patients, with no control group or odds ratio establishing enrichment.
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Reasoning
Governing specification: no AXIN2 ClinGen CSPEC/VCEP is available for this case (cspec.found = false; framework_mode = generic_acmg; gene_vcep_dir = null), so the generic ACMG/AMP 2015 criteria (Richards et al., PMID:25741868) apply and NO gene-specific numeric enrichment threshold exists for PS4. Because no numeric threshold is defined, there is no governing operator (>=/<=/>/<) to quote and no inequality to substitute; the criterion is judged against its generic definition (case-control enrichment of the variant in affected versus unaffected individuals). The exact variant NM_004655.4:c.203G>A p.(Arg68Gln) (rs138056036) is named in exactly one full-text source, PMID:31285513, a Spanish attenuated adenomatous polyposis (AAP) cohort of 158 unrelated patients in which it was detected once — heterozygous, patient ID 79, Table 2 — and classified class 3 (variant of uncertain significance) by ACMG-SHERLOC; the paper explicitly reports no actionable/class 4-5 AXIN2 finding. That report contains no control group, no odds ratio, no case-control frequency comparison and no enrichment analysis (searches of the full text for 'control', 'case-control', 'odds ratio' and 'enrich' returned nothing), so a defensible enrichment statistic cannot be derived — 1/158 carriers in an AAP cohort versus a gnomAD background is a raw case observation, not case-control enrichment. The remaining variant-specific sources are equally negative: PMID:28944238 (1231 colorectal cancer cases / 93 unaffected controls) and PMID:27153395 do not name the variant at all, and PMID:25394175 and PMID:38136308 are referral/prevalence documents with no AXIN2 variant data. gnomAD shows the allele at low but non-zero frequency in the general population (v2.1 AF = 0.0001347; v4.1 AF = 0.0001312), which neither establishes nor excludes enrichment. PS4 is therefore not met.
Rule
Generic ACMG/AMP 2015 PS4 (Richards et al., PMID:25741868): case-control enrichment of the variant in affected versus unaffected individuals; no gene-specific numeric threshold is available for AXIN2.
Evidence considered
No AXIN2 CSPEC or VCEP document exists for this case (cspec found = false; framework_mode = generic_acmg), so generic ACMG/AMP 2015 criteria were applied and no gene-specific numeric threshold or operator applies to PS4.
PMID:31285513 reports the exact variant (c.203G>A p.(Arg68Gln), rs138056036) once in 158 unrelated attenuated adenomatous polyposis patients (patient ID 79, Table 2), heterozygous, classified class 3 / VUS under ACMG-SHERLOC, and not among the actionable class 4-5 findings.
Full-text search of PMID:31285513 for 'control', 'case-control', 'odds ratio' and 'enrich' returned no matches: the study reports no control group and no enrichment statistic.
PMID:28944238 (1231 CRC cases, 93 unaffected controls) and PMID:27153395 do not name c.203G>A or p.Arg68Gln; both were checked and contribute no variant-specific case or control counts.
PMID:25394175 (ACMG/NSGC cancer-referral practice guideline) and PMID:38136308 (VUS prevalence in HBOC/Lynch testing) contain no AXIN2 or variant-specific data; PMID:38136308 has no retrieved full text (abstract only).
gnomAD v2.1 total AF = 0.0001347 (37/274598 alleles) and v4.1 AF = 0.0001312 (210/1600510 alleles), homozygotes = 0 — a low general-population frequency that is not case-control enrichment evidence.
Still missing
No case-control or cohort-enrichment study reports the frequency of AXIN2 c.203G>A in affected individuals versus controls, so no odds ratio (or any threshold comparison) could be computed.
No gene-specific PS4 numeric threshold exists: no AXIN2 ClinGen CSPEC or VCEP specification is available for this case (framework_mode = generic_acmg).
PM1Not 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.
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Reasoning
PM1 requires a mutational hotspot and/or a critical, well-established functional domain without benign variation (Richards et al. 2015, PMID:25741868). No gene-specific specification governs AXIN2: the case runs on the generic ACMG fallback (final_classification_framework.found=false, scoring_model 'ACMG/AMP 2015') and the governing materials contain no approved domain list for the gene (vcep_materials.json domain_tables is empty), so there is no ratified critical-domain set against which residue 68 can be scored. CancerHotspots returned no statistically significant hotspot at AXIN2 R68, and the residue is not variation-free: the variant itself is present in gnomAD v2.1 (AF 0.000135, 37/274,598 alleles) and gnomAD v4.1 (AF 0.000131, 210/1,600,510 alleles) with zero homozygotes and a popmax of 0.000404 in Admixed American. The variant does fall in the conserved N-terminal tankyrase-binding region, annotated to the SMART protein domain 'AXIN1_TNKS' in PMID:31285513, which is the strongest domain-based argument for PM1, but no governing framework designates that region as a critical domain and the region demonstrably tolerates missense change. PM1 is not met; flagged for human review because a reviewer may argue a domain-based interpretation from the literature annotation alone.
vcep_materials.json domain_tables is empty (no entry for AXIN2) and final_classification_framework found=false with source 'generic_acmg_fallback', so no approved critical functional-domain list governs this variant and PM1 defaults to the generic ACMG definition.
PMID:31285513 Table 2 annotates c.203G>A p.(Arg68Gln) to protein domain 'AXIN1_TNKS' (tankyrase-binding region), one of the four conserved AXIN2 domains (TMKS/RGS/beta-catenin-binding/DIX).
CancerHotspots lookup for 'AXIN2 R68' returned no result: 'This variant does not lie in a statistically significant hotspot.'
gnomAD v2.1: AF 0.0001347 (37/274,598 alleles, 0 homozygotes, popmax Admixed American 0.0002577); gnomAD v4.1: AF 0.0001312 (210/1,600,510 alleles, 0 homozygotes, popmax Admixed American 0.0004039) - the residue is not devoid of benign missense variation.
ClinVar 127940 contains no expert-panel assertion that would establish residue 68 or its region as a critical domain.
Still missing
No VCEP/CSPEC-approved critical-domain table exists for AXIN2 (vcep_materials.json domain_tables is empty), so the functional significance of the TNKS region at residue 68 rests on literature annotation rather than a governing specification.
A gene-specific specification would be required to apply PM1 on domain grounds; none is available for this case.
PM2Not 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.
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Reasoning
PM2 (supporting) applies to a variant that is absent or at extremely low frequency in population databases, applied at the supplied generic supporting threshold of <= 0.0001 (1e-4). This variant is not that rare. gnomAD v4.1 all-comers AF = 0.000131208 (210/1,600,510 alleles) and gnomAD v2.1 all-comers AF = 0.000134742 (37/274,598 alleles); the v4.1 exome-only AF is 0.000124982 and genome-only AF is 0.000190411, the v2.1 exome-only AF is 0.000148026. Even the lowest of these, the v4.1 exome AF, remains above 1e-4, and every ranking statistic is higher still: v4.1 grpmax joint FAF 0.00027822, v2.1 grpmax FAF 0.00015724, and top ancestry Admixed American 0.000403918 (v4.1) / 0.000257658 (v2.1). An independent published gnomAD European (non-Finnish) frequency of 2e-04 for this exact variant (PMID:31285513) is also above the threshold. Under the generic ACMG/ClinGen-SVI supporting threshold the variant exceeds 1e-4 by roughly 1.3-fold on the all-comers totals, so PM2 supporting is not met. No AXIN2 VCEP/CSPEC specification and no non-cancer-cohort gnomAD subset are available, so the all-comers totals are the applicable default.
Rule
gnomAD AF <= 0.0001 for supporting PM2 (generic ClinGen SVI default, PMID:25741868)
Evidence considered
gnomAD v4.1: total AF 0.000131208 (210/1,600,510 alleles); exome-only AF 0.000124982 (181/1,448,208), genome-only AF 0.000190411 (29/152,302); grpmax joint FAF 0.00027822; highest subpopulation Admixed American AF 0.000403918.
gnomAD v2.1: total AF 0.000134742 (37/274,598 alleles); exome-only AF 0.000148026 (36/243,200), genome-only AF 0.0000318492 (1/31,398); grpmax FAF 0.00015724; highest subpopulation Admixed American AF 0.000257658.
Lorca et al. 2019 (PMID:31285513) reports this exact variant (c.203G>A, p.(Arg68Gln), rs138056036) as heterozygous in one attenuated adenomatous polyposis patient and gives its gnomAD European (non-Finnish) Exome+Genome frequency as 2e-04, independently above the 1e-4 PM2 supporting threshold; the corresponding current v2.1 NFE frequency is 26/125,690 = 2.07e-04.
PM2 supporting threshold of <= 0.0001 applied as the supplied generic ClinGen SVI default (PMID:25741868); no AXIN2 VCEP/CSPEC specification exists to override it (cspec not found; framework_mode generic_acmg).
No non-cancer-cohort gnomAD subset was present for this case, so the all-comers GNOMAD_V2_1/GNOMAD_V4_1 totals were used as the default population source.
Still missing
The variant lies only ~1.3-fold above the generic 1e-4 PM2 supporting threshold (v4.1 all-comers AF 1.31e-4); no AXIN2-specific PM2 frequency threshold exists, so a gene-specific threshold could change this call.
No gnomAD non-cancer-cohort subset (GNOMAD_V2_1_NON_CANCER exomes / GNOMAD_V3_1_NON_CANCER genomes) was available for this cancer-predisposition gene; all-comers totals were used because no VCEP specification mandates a non-cancer or exome-only source.
PM3Not met: no pathogenic AXIN2 allele in trans, and 0 homozygotes among 37/274,598 gnomAD v2.1 alleles.
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Reasoning
PM3 (Richards et al. 2015, PMID:25741868) is met only for a recessive disorder when the variant is detected in trans with a pathogenic variant. NM_004655.4:c.203G>A (NP_004646.3:p.(Arg68Gln)) is a heterozygous missense change in AXIN2, and no pathogenic allele has ever been observed in trans with it. The single reported carrier of this exact variant (patient ID 79 in PMID:31285513, a 158-patient attenuated adenomatous polyposis cohort) was heterozygous for it, and that study's Table 2 states 'All variants were heterozygous'; the cohort's only other AXIN2 variant, c.2141G>A p.(Arg714Gln), occurred in a different patient (ID 55), so no in-trans AXIN2 pair exists in the literature. The ClinVar record for this variant (variation 127940, 9 submissions) likewise contains no report of a second AXIN2 allele or of biallelic occurrence. Population data agree: gnomAD v2.1 lists 37/274,598 alleles with 0 homozygotes, i.e. the variant has never been seen in the homozygous state. In addition, the AXIN2 disease context in which this variant was found is not a recessive one - the reported carriers are heterozygous and no AXIN2-associated recessive disorder is documented in the retrieved literature - so PM3's recessive premise is independently unmet. No ClinGen CSPEC/VCEP exists for AXIN2 (framework_mode = generic_acmg), so the generic ACMG/AMP 2015 definition was applied.
Rule
PM3: detected in trans with a pathogenic variant (recessive disorders) - Richards et al. 2015, PMID:25741868
Evidence considered
PMID:31285513 reports NM_004655.4:c.203G>A p.(Arg68Gln) (rs138056036) in one attenuated adenomatous polyposis patient (ID 79) as a heterozygous ACMG-SHERLOC class-3 (uncertain significance) variant located in the AXIN1_TNKS domain; the Table 2 footnote states 'All variants were heterozygous.'
PMID:31285513 Table 2 contains only two AXIN2 variants in the entire 158-patient cohort - c.2141G>A p.(Arg714Gln) in patient ID 55 and c.203G>A p.(Arg68Gln) in patient ID 79 - i.e. they occur in different individuals, so this variant was never observed in trans with another AXIN2 variant.
ClinVar variation 127940: 9 submissions (6 clinical laboratories uncertain significance; 1 likely benign; 1 likely benign; plus further single-submitter records); no submission reports a coexisting AXIN2 pathogenic allele, biallelic status, or phase information.
gnomAD v2.1 (exome+genome): total AC 37 / AN 274,598 (AF 0.000135); homozygote count 0; highest population frequency 0.000258 (Admixed American, 9/34,930) - no homozygous occurrence.
Richards et al. 2015 (PMID:25741868) defines PM3 for recessive disorders when the variant is detected in trans with a pathogenic variant, and notes PM3 'could be upgraded to strong if there were multiple observations of detection of the variant in trans (on opposite chromosomes) with other pathogenic variants'; the prerequisite in-trans pathogenic allele is absent for this variant.
Framework: no ClinGen CSPEC/VCEP or local gene framework exists for AXIN2 in this case, so generic ACMG/AMP 2015 criteria (PMID:25741868) were applied.
No phase, trio, or second-variant data for this variant were found in any retrieved source (ClinVar submissions, gnomAD, or the fetched full texts).
Still missing
No phasing, parental genotype, or second AXIN2 variant data are available for the single reported carrier (patient ID 79, PMID:31285513); PM3 could only become applicable if a pathogenic AXIN2 allele were demonstrated on the opposite chromosome.
PM5Not met: no missense change other than p.Arg68Gln is reported at codon 68, so the required pathogenic same-residue comparator does not exist.
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Reasoning
PM5 requires a different missense change at the same residue (Arg68) to be established as pathogenic (Richards et al. 2015, PMID:25741868). The automated same-residue comparator harvest collected zero candidates and explicitly deferred the call (pm5_candidates.json: found=false, pm5_mode 'unknown', eligible_for_classic_pm5_search=false, 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting'), instructing that it must not be used alone to apply PM5. Manual review of every source in this case confirms there is no comparator: ClinVar 127940 lists only the c.203G>A p.Arg68Gln change, PMID:31285513 reports only p.(Arg68Gln) at residue 68 (class 3, uncertain significance), and the remaining fetched papers (PMID:28944238, PMID:27153395) name no AXIN2 codon-68 variant at all. With no established pathogenic missense at the same residue, PM5 cannot be met; the absence of a completed systematic codon-68 sweep is recorded as a gap.
Rule
ACMG/AMP 2015 PM5 (missense change at the same residue as a different established pathogenic missense) - PMID:25741868
Evidence considered
pm5_candidates.json: found=false, residue R68, pm5_mode 'unknown', eligible_for_classic_pm5_search=false, total_candidates_seen=0 and same_residue_candidates=0; the harvest was skipped and the artifact states PM5 must not be applied from it alone.
ClinVar variation 127940 lists only the c.203G>A p.Arg68Gln change; no other codon-68 missense variant is present in the record.
PMID:31285513 reports only p.(Arg68Gln) at residue 68, as class 3 (uncertain significance); no other AXIN2 residue-68 change is described.
PMID:28944238 and PMID:27153395 name no AXIN2 codon-68 variant at all; the only AXIN2 variant named in PMID:28944238 is the in-frame indel p.His474_Ser475insHis.
No same-residue pathogenic comparator was therefore available to evaluate, so PM5 is not met on the evidence in this case.
Still missing
The automated same-residue comparator harvest was skipped (pm5_mode 'unknown'); a systematic ClinVar search for other AXIN2 codon-68 missense variants (e.g. p.Arg68Trp/Leu/Pro) was not run and remains outstanding, though no such variant appears in any source examined here.
PP2Not 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.
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Reasoning
PP2 requires a missense variant in a gene in which missense change is a common mechanism of disease and benign missense variation is rare (Richards et al. 2015, PMID:25741868). AXIN2's established germline disease mechanism is loss of function through truncating variants: the gene-level PVS1 context artifact records lof_mechanism_supported=true with the rationale that the germline literature supports AXIN2 loss of function as a germline disease mechanism, and OncoKB's curated gene entry describes AXIN2 as a tumor suppressor whose truncating mutations are associated with colorectal cancer (variant-level curation for R68Q is 'Unknown Oncogenic Effect'). No evidence in this case establishes missense change as a common AXIN2 disease mechanism, and no missense-constraint metric (e.g. missense Z-score) is available to show a low rate of benign missense variation. Both halves of the PP2 premise are therefore unsatisfied.
Rule
ACMG/AMP 2015 PP2 (missense variant in a gene with a low rate of benign missense variation and where missense is a common disease mechanism) - PMID:25741868
Evidence considered
pvs1_gene_context: lof_mechanism_supported=true; mechanism_rationale states the targeted germline literature review identified publications supporting AXIN2 loss of function as a germline disease mechanism; cautions note that no official CSPEC/VCEP was available.
OncoKB gene-level curation for AXIN2: 'a tumor suppressor involved in WNT signaling'; background states 'Truncating mutations in AXIN2 have been associated with colorectal cancer'; the variant-level record for R68Q is 'Unknown Oncogenic Effect'.
Gene summary for AXIN2 describes it as a beta-catenin destruction-complex scaffold and tumor suppressor, with mutations linked to colorectal cancer and familial tooth agenesis with predisposition to colorectal cancer.
No missense constraint metric for AXIN2 was present in the case evidence, so a low rate of benign missense variation could not be demonstrated.
A functionally supported AXIN2 missense has been reported in isolated tooth agenesis (PMID:41361419, p.Thr693Met, aberrant Wnt/beta-catenin activation in vitro); a single such report does not establish missense change as a common AXIN2 disease mechanism.
Still missing
No gene-level missense constraint metric (missense Z-score or equivalent) for AXIN2 was available in this case, so the 'low rate of benign missense variation' half of PP2 could not be measured directly.
PP3Not met: REVEL 0.176 for p.(Arg68Gln) sits far below the >= 0.644 supporting PP3 threshold.
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Reasoning
PP3 requires computational evidence that supports a deleterious effect on the gene or gene product. NM_004655.4:c.203G>A is a missense substitution predicted to produce NP_004646.3:p.(Arg68Gln) (consequence_class = missense), so the applicable predictor path for PP3/BP4 is the missense protein-impact path, REVEL; the SpliceAI splice path is not applicable to a missense variant and was therefore not consulted, and SpliceAI's absent score was not used in either direction. The calibrated REVEL score for this change (chr17:g.65558418C>T, GRCh38, = NC_000017.10:g.63554536C>T) is 0.176, which is below the ClinGen SVI REVEL supporting PP3 cutoff of >= 0.644 (Pejaver et al. 2022, PMID:36413997) and therefore also below the moderate (>= 0.773) and strong (>= 0.932) cutoffs. The local BayesDel score (-0.262489) is present but no generic ACMG-strength BayesDel calibration is established, so it is treated as not available for PP3 rather than being counted as additional support. No ClinGen CSPEC specification and no VCEP/gene-specific framework exists for AXIN2 (framework_complete = false; fallback = generic ACMG/AMP 2015), so the generic thresholds apply without any gene-specific override. PP3 is therefore not met.
Rule
missense -> REVEL path; PP3 not met because REVEL 0.176 < 0.644 supporting cutoff (Pejaver et al. 2022, PMID:36413997)
Evidence considered
Consequence class: missense (NP_004646.3:p.(Arg68Gln)) - selects the REVEL missense path for PP3/BP4; the SpliceAI splice path is out of scope for this variant class.
REVEL v1.3 local lookup (revel block): score 0.176 for chr17:g.65558418C>T (GRCh38), i.e. the same allele as NC_000017.10:g.63554536C>T.
Threshold applied: PP3 supporting requires REVEL >= 0.644; moderate >= 0.773; strong >= 0.932 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, Am J Hum Genet, PMID:36413997). 0.176 falls below all three, so PP3 is not met.
BayesDel (-0.262489, local BayesDel_170824_noAF lookup) was noted but excluded: no generic ACMG-strength BayesDel calibration is established, so per instruction it is treated as not_available for PP3/BP4 and cannot support PP3.
SpliceAI returned no score for this variant (query timeout, max_delta_score null, Pangolin only); this is missing data and, being a missense variant, the splice path was never the applicable path - it was not used to support or refute PP3.
No ClinGen CSPEC record and no VCEP/gene-specific PP3-BP4 lookup material exists for AXIN2; generic ACMG/AMP 2015 with the published calibration thresholds governs.
PP5Not met: ClinVar record 127940 has zero expert-panel submissions and no Pathogenic or Likely pathogenic assertion for this exact variant.
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Reasoning
PP5 is only triggered by an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact-variant ClinVar record for this variant (ClinVar ID 127940, NM_004655.4(AXIN2):c.203G>A p.(Arg68Gln), exact transcription-level match) has zero expert-panel submissions: the submission audit reports expert_panel_submissions = 0 across 9 submissions, and every usable submission is flagged is_expert_panel = false. The aggregate record is Uncertain significance (six clinical laboratories) with two Likely benign laboratory submissions; no Pathogenic or Likely pathogenic assertion of any kind exists at the variant level, from an expert panel or otherwise. The variant-level publications cited by those submissions (PMID:28944238, PMID:31285513, PMID:27153395, PMID:28492532, PMID:26467025, PMID:25394175, PMID:38136308) contain no external expert-panel classification of c.203G>A, and PMID:31285513 itself classifies it class 3 / VUS under ACMG-SHERLOC. Ordinary laboratory submissions and aggregate ClinVar labels must never trigger PP5, so with no expert-panel Pathogenic/Likely pathogenic assertion the criterion is not met. No numeric threshold applies to PP5 (no AXIN2 VCEP/CSPEC exists), so no operator comparison is required.
Rule
PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic (applied at supporting strength when satisfied); ordinary laboratory submissions and aggregate ClinVar labels do not trigger it.
Evidence considered
Exact-variant ClinVar record 127940 (NM_004655.4(AXIN2):c.203G>A p.(Arg68Gln)) matched by transcript HGVS; submission audit counts expert_panel_submissions = 0 and marks all submissions is_expert_panel = false.
Aggregate ClinVar classification is Uncertain significance (6 clinical laboratories) plus 2 ordinary-laboratory Likely benign submissions; no Pathogenic or Likely pathogenic assertion exists.
PMID:31285513, the only paper naming this variant, classifies it class 3 / variant of uncertain significance by ACMG-SHERLOC criteria.
BA1Not met: gnomAD v4.1 AF 0.000131 and v2.1 AF 0.000135 are roughly two orders of magnitude below the 5% BA1 threshold.
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Reasoning
BA1 requires a stand-alone benign allele frequency of >= 0.05 (5%) (Richards et al. 2015, PMID:25741868). The variant is a rare, established low-frequency missense: gnomAD v2.1 total AF = 0.000134742 (37/274,598 alleles) and gnomAD v4.1 total AF = 0.000131208 (210/1,600,510 alleles). Its highest observed ancestry-specific frequency is Admixed American (v2.1 AF 0.000257658, 9/34,930 alleles; v4.1 AF 0.000403918, 24/59,418 alleles), and the grpmax filtering allele frequency is 0.00015724 (v2.1) and 0.00027822 (v4.1). Every one of these values is roughly two orders of magnitude below the 5% threshold. AXIN2 is associated with a rare autosomal dominant oligodontia-colorectal cancer predisposition; no plausible disease prevalence could justify relaxing a 5% stand-alone frequency to the observed 0.013% level. No homozygotes are reported in either dataset. BA1 is therefore not met.
Rule
gnomAD highest AF (or grpmax FAF) >= 0.05 for stand-alone benign (PMID:25741868)
Evidence considered
gnomAD v2.1 (GRCh37, 17-63554536-C-T): total AF 0.000134742, 37/274,598 alleles, 0 homozygotes; grpmax FAF 0.00015724; highest subpopulation Admixed American AF 0.000257658 (9/34,930).
gnomAD v4.1 (GRCh38, chr17-65558418-C-T): total AF 0.000131208, 210/1,600,510 alleles, 0 homozygotes; grpmax joint FAF 0.00027822; highest subpopulation Admixed American AF 0.000403918 (24/59,418).
BA1 stand-alone threshold >= 0.05 published in the ACMG/AMP 2015 sequence variant interpretation standards (PMID:25741868), applied verbatim as supplied; no AXIN2 VCEP/CSPEC specification exists to override it (cspec not found; framework_mode generic_acmg).
gnomAD-Canada v1.0 reports the variant as not available, so no additional population source is informative.
AXIN2 disease context (rare, adult-onset, incompletely penetrant colorectal cancer / tooth agenesis predisposition) provides no prevalence argument that would lower a 5% stand-alone frequency to the observed ~0.013%.
BS1Not met: the highest gnomAD frequency, v4.1 grpmax FAF 0.000278, is ~36-fold below the 1% BS1 threshold.
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Reasoning
BS1 (strong benign) requires an allele frequency greater than expected for the disorder, applied here at the supplied generic default of >= 0.01 (1%) (PMID:28518168 as the per-gene derivation model; the case has no AXIN2-specific frequency derivation). The gnomAD v2.1 total AF is 0.000134742 and the v4.1 total AF is 0.000131208; the highest ancestry-specific frequency is Admixed American at 0.000257658 (v2.1) and 0.000403918 (v4.1); the grpmax FAF is 0.00015724 (v2.1) and 0.00027822 (v4.1). Even the most frequent subpopulation value is ~25-fold below the 1% threshold. A published independent gnomAD European (non-Finnish) frequency of 2e-04 for this variant (PMID:31285513) is of the same order and likewise far below threshold. BS1 is not met.
Rule
gnomAD highest AF (or grpmax FAF) >= 0.01 for strong benign, per-gene derivation preferred (PMID:28518168)
Evidence considered
gnomAD v2.1: total AF 0.000134742 (37/274,598), grpmax FAF 0.00015724, highest subpopulation Admixed American 0.000257658.
gnomAD v4.1: total AF 0.000131208 (210/1,600,510), grpmax joint FAF 0.00027822, highest subpopulation Admixed American 0.000403918.
Lorca et al. 2019 (PMID:31285513) reports this exact variant (c.203G>A, p.(Arg68Gln), rs138056036) at a European (non-Finnish) gnomAD frequency of 2e-04, independently corroborating that the variant is not more common than the v2.1/v4.1 totals indicate.
BS1 threshold of >= 0.01 (1%) used as the supplied generic SVI default (per-gene derivation preferred, Whiffin et al. 2017, PMID:28518168); no AXIN2 specification exists to override it.
Still missing
No AXIN2/gene-specific BS1 frequency derivation exists (no VCEP/CSPEC); the generic 1% default was used, and a gene-specific derivation calibrated to AXIN2 disease prevalence could in principle shift this threshold.
BS2Not met: zero homozygotes in gnomAD v2.1 (37 alleles) and v4.1 (210 alleles), and AXIN2 disease is adult-onset with incomplete penetrance.
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Reasoning
BS2 requires the variant to have been observed in a healthy adult individual (homozygous for a recessive disorder, heterozygous for a fully penetrant dominant disorder, or hemizygous for an X-linked disorder) in a context incompatible with the disease. gnomAD reports zero homozygotes for this variant in both datasets despite substantial allele counts: v2.1 has 37/274,598 alleles with total_hom = 0 (including 0 homozygotes across every ancestry subpopulation), and v4.1 has 210/1,600,510 alleles with total_hom = 0 (Admixed American 24 alleles, homozygote_count 0). There is therefore no recorded homozygous carrier to support BS2. In addition, the AXIN2-associated disorder (oligodontia with colorectal cancer predisposition) is adult-onset with incomplete penetrance, so the criterion's premise of 'full penetrance expected at an early age' is not satisfied for a heterozygous observation. BS2 is not met.
Rule
Observed in a healthy adult individual (homozygous / fully penetrant heterozygous / hemizygous) incompatible with disease (Richards et al. 2015, PMID:25741868)
Evidence considered
gnomAD v2.1: total_hom = 0 (exome_hom 0, genome_hom 0); every ancestry subpopulation reports homozygote_count 0 (e.g. Admixed American ac 9, an 34,930, homo 0).
gnomAD v4.1: total_hom = 0 (exome_hom 0, genome_hom 0); every ancestry subpopulation reports homozygote_count 0 (e.g. Admixed American ac 24, an 59,418, homo 0).
AXIN2-associated disease (oligodontia-colorectal cancer predisposition) is an adult-onset, incompletely penetrant autosomal dominant condition, so a heterozygous observation does not meet BS2's requirement of a healthy adult for a disorder with full penetrance at an early age.
Still missing
No genotype-level healthy-adult cohort data beyond gnomAD was available; the zero homozygote count is the sole basis for this call, and absence of observed homozygotes reflects both variant rarity and limited cohort size.
BS3Not met: no functional assay of AXIN2 p.Arg68Gln exists - the only protein-function statements are in-silico (ClinVar SCV000149781, SCV002584759), which cannot satisfy BS3.
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Reasoning
BS3 requires well-established functional studies showing that the variant has no damaging effect on protein or gene function. No functional assay of any kind has been performed on AXIN2 NM_004655.4:c.203G>A p.(Arg68Gln). The functional status asserted in the ClinVar record is purely computational: GeneDx (SCV000149781) states 'in silico analysis indicates that this missense variant does not alter protein structure/function', and St. Jude (SCV002584759) states that the benign in-silico prediction 'has not been confirmed by functional studies'. ACMG/AMP in-silico predictor output is not a functional assay and cannot be used to satisfy BS3; it belongs to the PP3/BP4 evidence path. The only publication naming the variant (PMID:31285513) classified it as a class-3 VUS with no functional testing. The gene-level AXIN2 assays present in the case artifacts (pvs1_gene_context; PMID:41361419) were performed on other variants (c.2078C>T p.Thr693Met, c.1060-3T>C) and are not transferable to codon 68. OncoKB records no variant-specific reviewed functional evidence. BS3 is therefore not met - there is no assay-derived evidence of normal function, only absence of assay data. No ClinGen CSPEC/VCEP specification exists for AXIN2, so the generic ACMG/AMP 2015 BS3 definition (PMID:25741868) governs.
Rule
BS3 (generic ACMG/AMP 2015, PMID:25741868): well-established functional studies show no damaging effect. In-silico predictions and population/somatic observations do not satisfy this criterion; no AXIN2-specific VCEP/CSPEC strength calibration exists.
Evidence considered
ClinVar submitter GeneDx (SCV000149781) backs its Likely-benign-leaning position only with in-silico reasoning: 'in silico analysis indicates that this missense variant does not alter protein structure/function'. In-silico predictor output is excluded from BS3 by definition (and by the ACMG/AMP single-piece-of-evidence rule for computational predictors), so this cannot support BS3.
ClinVar submitter St. Jude Molecular Pathology (SCV002584759) records the same limitation explicitly for this variant: the REVEL-based prediction of a benign effect 'has not been confirmed by functional studies'.
OncoKB reports classification 'Unknown Oncogenic Effect' and no variant-specific reviewed functional evidence for AXIN2 R68Q, so no curated assay data exist on the benign side either.
Lorca et al. 2019 (PMID:31285513, Table 2, patient ID 79) listed c.203G > A p.(Arg68Gln) as class 3 (ACMG-SHERLOC VUS) in a 158-patient attenuated polyposis cohort; the paper reports no functional assay, so it provides no BS3 evidence.
Gene-level AXIN2 functional data in the case artifacts (pvs1_gene_context; PMID:41361419) show assays were run only on c.2078C>T p.(Thr693Met) and c.1060-3T>C; no assay, reporter, or expression result exists for p.Arg68Gln, so no normal-function claim can be assay-grounded.
Searched all screened sources for assay-based functional evidence on this variant using 'c.203G>A', 'p.(Arg68Gln)', 'p.R68Q', 'R68Q' and 'rs138056036'; only computational predictions and population observations were returned.
Governing framework: no ClinGen CSPEC or AXIN2-specific VCEP exists (case_summary.cspec.found = false; vcep_materials.final_classification_framework.source = 'generic_acmg_fallback'), so BS3 is assessed under the generic ACMG/AMP 2015 definition (PMID:25741868).
Still missing
No functional assay demonstrating preserved (non-damaging) AXIN2 function for p.Arg68Gln exists in any reviewed source; the BS3 verdict rests on the absence of assay evidence, not on a negative assay.
Validated AXIN2 assay systems do exist for other variants (Wnt/beta-catenin activation and PBMC mRNA assays in PMID:41361419), so a targeted assay of codon 68 is technically feasible if a laboratory chooses to resolve this VUS experimentally.
BP2Not met: no pathogenic AXIN2 variant reported in cis or in trans with c.203G>A; the single carrier was heterozygous for this variant alone.
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Reasoning
BP2 (Richards et al. 2015, PMID:25741868) is met when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern. Neither condition is satisfied for NM_004655.4:c.203G>A. No pathogenic (class 4/5) AXIN2 variant is reported on either chromosome together with this change anywhere in the evidence: PMID:31285513 detected it as an isolated heterozygous class-3 (uncertain significance) finding in a single attenuated adenomatous polyposis patient, with no accompanying AXIN2 variant in that individual and no phasing performed in a cohort in which every validated variant was heterozygous; the ClinVar record (variation 127940) contains 9 submissions, none of which reports a coexisting pathogenic AXIN2 allele or any cis/trans configuration. Because no pathogenic variant exists in cis or in trans with c.203G>A, the criterion has nothing to test and cannot be met. Population data are consistent with a single-allele-only observation: gnomAD v2.1 shows 37/274,598 alleles with 0 homozygotes. No ClinGen CSPEC/VCEP exists for AXIN2 (framework_mode = generic_acmg), so the generic ACMG/AMP 2015 definition was applied.
Rule
BP2: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern - Richards et al. 2015, PMID:25741868
Evidence considered
PMID:31285513 reports c.203G>A p.(Arg68Gln) as a heterozygous class-3 variant in a single attenuated adenomatous polyposis patient (ID 79) with no second AXIN2 variant in that individual; the AXIN2 variant c.2141G>A was found in a different patient (ID 55), and the paper states all validated variants were heterozygous.
ClinVar variation 127940 (9 submissions, none from an expert panel): no submission describes a pathogenic AXIN2 variant in cis or in trans with c.203G>A, and no submission reports phase information.
gnomAD v2.1: 37/274,598 alleles observed, homozygote count 0 - the variant has only ever been observed on a single allele in this dataset.
Richards et al. 2015 (PMID:25741868) defines BP2 as 'observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder' or 'observed in cis with a pathogenic variant in any inheritance pattern'; neither configuration is documented for this variant.
Framework: no ClinGen CSPEC/VCEP or local framework exists for AXIN2 in this case, so generic ACMG/AMP 2015 criteria (PMID:25741868) were applied.
Still missing
No phase data (trio, long-read, or allele-specific) exist for this variant; BP2 could only be met if a pathogenic AXIN2 variant were demonstrated in cis (any inheritance pattern) or, for a fully penetrant dominant disorder, in trans with it.
BP5Not met: no affected individual carrying this variant has a documented alternate molecular basis for disease in any reviewed source.
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Reasoning
Generic ACMG/AMP 2015 BP5 (Richards et al., PMID:25741868) requires that the variant be found in a case with an alternate molecular basis for the disease. No such case is documented: the only reported carrier of c.203G>A, patient ID 79 in PMID:31285513 (Table 2), is listed solely under AXIN2, with no co-occurring pathogenic APC or MUTYH variant or other alternate genetic diagnosis recorded, and the paper reports that screening of candidate genes found no causative mutation among the unexplained adenomatous polyposis patients. The case records contain no proband-level data (no phenotype, segregation, co-occurrence or second-variant information) that could establish an alternate molecular basis, and no evidence source describes a patient with this variant in whom the disease is attributable to another gene. No numeric threshold, and therefore no comparison operator, applies to BP5 here: no AXIN2 ClinGen CSPEC or VCEP exists for this case (framework_mode = generic_acmg), so no gene-specific likelihood-ratio-style BP5 value or cutoff is defined. With no documented alternate molecular basis, BP5 is not met.
Rule
Generic ACMG/AMP 2015 BP5 (Richards et al., PMID:25741868): variant found in a case with an alternate molecular basis for disease; no gene-specific numeric threshold is available for AXIN2.
Evidence considered
PMID:31285513 Table 2 lists patient ID 79 only once, under AXIN2 (c.203G>A p.(Arg68Gln)); no co-occurring pathogenic APC or MUTYH variant is reported for that patient.
No numeric BP5 threshold or operator applies: no AXIN2 ClinGen CSPEC/VCEP specification exists for this case, so generic ACMG/AMP 2015 BP5 semantics are used.
ClinVar submissions for this variant carry no case-level alternate-diagnosis information, and no other evidence source describes a carrier with an alternate molecular basis.
Still missing
No proband-level clinical or segregation data are available (no phenotype, co-occurring variant or alternate genetic diagnosis), so a case with an alternate molecular basis could not be identified or excluded beyond the single reported carrier.
BP6Not met: the two Likely benign ClinVar submissions for this variant are ordinary laboratory assertions, with zero expert-panel submissions on record.
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Reasoning
BP6 is only triggered by an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact-variant ClinVar record (ClinVar ID 127940, NM_004655.4(AXIN2):c.203G>A p.(Arg68Gln), exact match) contains two Likely benign submissions — Ambry Genetics (SCV001174863) and Quest Diagnostics Nichols Institute San Juan Capistrano (SCV005624959) — but both are flagged is_expert_panel = false, i.e. ordinary clinical-laboratory submissions, and the submission audit reports expert_panel_submissions = 0. The aggregate record is Uncertain significance (six clinical laboratories); the Likely benign calls are a minority of submitters and are not expert-panel assertions. Per the governing requirement that only an exact-variant expert-panel Benign/Likely benign classification may trigger BP6, and that ordinary laboratory submissions and aggregate labels must never trigger it, BP6 is not met. No numeric threshold applies to BP6 (no AXIN2 VCEP/CSPEC exists), so no operator comparison is required or performed.
Rule
BP6 requires an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary laboratory submissions and aggregate ClinVar labels do not trigger it.
Evidence considered
Exact-variant ClinVar record 127940 has two Likely benign submissions (Ambry Genetics SCV001174863; Quest Diagnostics SCV005624959), both flagged is_expert_panel = false.
Submission audit for this record: submissions_total = 9, expert_panel_submissions = 0, aggregate classification Uncertain significance (6 clinical laboratories).
Ordinary laboratory submissions and aggregate ClinVar labels are explicitly excluded from triggering BP6 under the governing requirement.
PS2Not assessed: no proband or parental testing exists in any source, and the sole variant report (PMID:31285513) provides no parental genotype data.
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Reasoning
PS2 (de novo, both maternity and paternity confirmed) requires a proband affected with the disease in whom the variant arose de novo, with parental identity confirmed by testing (Richards et al. 2015, PMID:25741868). This case is variant-level only: there is no proband, no parental genotype or testing result, no family history, and no meiosis count anywhere in the case record or in any reviewed source. The ClinVar record for this variant (ClinVarID 127940, VCV000127940; 9 germline submissions, 0 expert-panel submissions) carries no trio or family-history data on any submission. PMID:31285513, the only source that names this exact variant (AXIN2 c.203G>A, p.Arg68Gln, rs138056036), is a cohort study that detected it once in an adult attenuated adenomatous polyposis patient (ID 79), without parental testing, without a family description, and with a class-3 (variant of uncertain significance) classification; it reports no de novo occurrence. A targeted screen of all reviewed full texts and of the ClinVar submission detail for 'de novo', 'parental', 'trio', 'family', 'affected relative', 'proband' and 'meiosis' content returned nothing. The variant is additionally present in gnomAD (37 alleles, 0 homozygotes, total AF 1.35e-4), i.e. it is demonstrably transmitted in the general population, so any de novo claim for a specific proband would require explicit parental testing rather than being assumed. Because the required proband-plus-parents evidence is absent rather than contradicted, PS2 cannot be evaluated and is recorded as not assessed. No ClinGen CSPEC or gene-specific VCEP specification exists for AXIN2 (framework_complete=false), so generic ACMG/AMP 2015 applies.
Evidence considered
PS2 definition applied per Richards et al. 2015 (PMID:25741868): de novo in a patient with the disease, with both maternity and paternity confirmed.
The case record is variant-level only: no proband, no parental genotypes, no parental testing, no family history, and no meiosis count are present in the case summary, the evidence record, or the literature pass.
The ClinVar record (ClinVarID 127940) lists 9 germline submissions from 9 submitters with no expert-panel review and no trio, family-history, or inheritance data on any submission.
PMID:31285513 is the only source that names this exact variant (rs138056036; NM_004655.4:c.203G>A; p.Arg68Gln). It reports a single heterozygous occurrence in an adult attenuated adenomatous polyposis patient (ID 79), classified as class-3 (variant of uncertain significance) by ACMG-SHERLOC, with no parental testing and no de novo statement.
All six full-text sources and the ClinVar submission detail were screened for de novo, parental, trio, family, affected-relative, proband and meiosis content; no such data exist for this variant.
The variant is present in gnomAD v2.1 (37/274598 alleles, 0 homozygotes, total AF 1.35e-4; Admixed American AF 2.58e-4), indicating population transmission and making an assumed de novo origin untenable without explicit trio data.
Generic ACMG/AMP 2015 fallback applies: no ClinGen CSPEC is available for AXIN2 and no gene-specific VCEP framework governs this case (framework_complete=false).
Still missing
No proband identified and no parental genotypes or parental-testing results reported; confirmed de novo status (both maternity and paternity) cannot be established.
No family-history information for any carrier of AXIN2 c.203G>A, including the single affected proband (ID 79) in PMID:31285513.
A trio (proband plus both parents) with confirmed parentage is required to resolve PS2; if obtained, re-adjudicate PS2 before PM6.
PM6Not assessed: no parental testing or family data exist anywhere, and the sole variant report (PMID:31285513) documents no assumed de novo event.
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Reasoning
PM6 (assumed de novo, but without confirmation of paternity and maternity) requires that the variant be present in an affected proband and absent in the parents by history or parental testing, such that a de novo origin is assumed rather than proven (Richards et al. 2015, PMID:25741868). The weaker evidentiary path PM6 offers is still a proband-level, parent-level observation, and this case contains neither. No proband is described, no parental status (tested, untested, negative, positive) is reported for any carrier, and no source states or implies that the variant arose de novo. PMID:31285513, the only source reporting this exact variant (c.203G>A, p.Arg68Gln, rs138056036), reports it once in an adult attenuated adenomatous polyposis patient (ID 79) with no parental information and no de novo assumption, classifying it as class-3 (variant of uncertain significance). The ClinVar record (ClinVarID 127940) contains 9 germline submissions but no trio or inheritance information, and no submission asserts de novo status. Because the minimum observation needed for even the assumed-de-novo path is missing, PM6 is recorded as not assessed rather than not met. Note that PM6 is not a fallback for PS2 in the absence of data: without any parental information there is nothing to 'assume' de novo from. Generic ACMG/AMP 2015 applies (no ClinGen CSPEC for AXIN2; framework_complete=false).
Evidence considered
PM6 definition applied per Richards et al. 2015 (PMID:25741868): assumed de novo, but without confirmation of paternity and maternity.
No source states or implies a de novo origin for AXIN2 c.203G>A; the searched terms 'de novo', 'parental', 'trio', 'family', 'affected relative', 'proband' and 'meiosis' return no matches across the reviewed evidence.
PMID:31285513 reports this variant (rs138056036) in one adult attenuated adenomatous polyposis patient (ID 79), heterozygous, class-3 (variant of uncertain significance), with no parental or family data and no de novo claim.
The ClinVar record (ClinVarID 127940) provides no inheritance or parental-status information across its 9 germline submissions and no expert-panel assertion.
The variant is present in gnomAD v2.1 (37/274598 alleles, 0 homozygotes, total AF 1.35e-4) and was found in an unrelated adult cohort, evidence that the allele is transmitted in the population; assuming de novo status in any single proband without parental data would be unsupported.
Generic ACMG/AMP 2015 fallback applies: no ClinGen CSPEC is available for AXIN2 and no gene-specific VCEP framework governs this case (framework_complete=false).
Still missing
No parental status for any carrier of AXIN2 c.203G>A: parents are neither tested nor reported negative/positive, so an assumed de novo origin cannot be recorded.
No proband-level clinical description (disease, age, phenotype) accompanies the one reported occurrence of this variant.
Parental testing (even without full trio parentage confirmation) would allow PM6 to be adjudicated; it should be requested if available.
PP1Not assessed: no pedigree or genotyped affected relative exists in any source, so zero informative co-segregation meioses can be counted for c.203G>A.
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Reasoning
PP1 (co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease) requires a family in which the variant is present in multiple affected relatives and the number of informative meioses is documented (Richards et al. 2015, PMID:25741868). No pedigree, no genotyped affected relative, and no informative meiosis exist for AXIN2 c.203G>A in this case: every carrier identified in the literature is described as an unrelated index patient, and the case record itself contains no family data. PMID:31285513 reports the variant once in a single attenuated adenomatous polyposis patient (ID 79) from a cohort of 158 unrelated Spanish patients, explicitly stating no actionable AXIN2 findings and no family segregation analysis; PMID:28944238 sequenced AXIN2 in 1231 colorectal cancer cases and 93 controls but reports only gene-level commentary (a single predicted-damaging Tier 2 variant among 36 genes) and never names this variant, with no co-segregation analysis. The ClinVar record (ClinVarID 127940) contains no pedigree or segregation information. Because co-segregation evidence is entirely absent rather than contradicted, PP1 is recorded as not assessed. Whether AXIN2 is 'definitively known to cause the disease' is likewise unsettled here: no ClinGen CSPEC exists for AXIN2 and the disease association rests on literature only, so generic ACMG/AMP 2015 applies (framework_complete=false).
Evidence considered
PP1 definition applied per Richards et al. 2015 (PMID:25741868): co-segregation with disease in multiple affected family members, in a gene definitively known to cause the disease.
PMID:31285513 reports AXIN2 c.203G>A p.(Arg68Gln) (rs138056036) in one attenuated adenomatous polyposis patient (ID 79) drawn from 158 unrelated patients; the study performs no family segregation analysis and explicitly reports no actionable AXIN2 findings.
PMID:28944238 sequenced AXIN2 (and 35 other colorectal cancer susceptibility genes) in 1231 colorectal cancer cases and 93 unaffected controls but provides only gene-level commentary about AXIN2 and never names c.203G>A, with no co-segregation data of any kind.
PMID:26467025 describes a rules-based scoring system that includes segregation as an evidence attribute, but reports no AXIN2 variant and no segregation data for this variant.
The ClinVar record (ClinVarID 127940) carries no pedigree, family, or segregation information on any of its 9 germline submissions.
All reviewed full texts and the ClinVar submission detail were screened for 'segregat', 'pedigree', 'family', 'affected relative', 'proband' and 'meiosis'; no matches exist for this variant.
Generic ACMG/AMP 2015 fallback applies: no ClinGen CSPEC is available for AXIN2 and no gene-specific VCEP framework governs this case (framework_complete=false).
Still missing
No pedigree or family structure reported for any carrier of AXIN2 c.203G>A.
No genotyping of affected or unaffected relatives, so no informative meioses and no co-segregation statistic can be computed.
Disease causality for AXIN2 remains literature-based only (no ClinGen CSPEC, no gene-specific VCEP framework), so the PP1 precondition of a gene definitively known to cause the disease is itself unverified for this case.
PP4Not 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.
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Reasoning
PP4 requires that the patient's phenotype or family history be highly specific for a disease with a single genetic etiology. No proband-level phenotype or family history is recorded anywhere in this case: review_manifest.json, case_summary.json and evidence_brief.json carry no clinical indication, HPO terms or family history for the individual in whom c.203G>A was found, and the ClinVar submissions for this variant list only generic conditions ('AXIN2-related condition', 'not provided', 'not specified', 'Not Provided') or no condition at all. The only disease context in the evidence is PMID:31285513, which places this variant inside a cohort of attenuated adenomatous polyposis (AAP) — a deliberately genetically heterogeneous syndrome that the paper itself attributes to APC, MUTYH, POLE, POLD1, NTHL1, MSH3 and AXIN2, and in which APC and MUTYH alone account for only 5-10% of cases. Even taken at face value, that referral phenotype would not be highly specific to a single genetic etiology, but because the case supplies no phenotype at all the criterion cannot be positively or negatively assessed. PP4 is therefore not assessed rather than met or not met; a curator would need the actual clinical indication and family history to resolve it. No VCEP/CSPEC specification exists for AXIN2 (generic ACMG/AMP 2015 applies; richards PMID:25741868), so no gene-specific phenotype checklist is available either.
Rule
Generic ACMG/AMP 2015 PP4 (Richards et al., PMID:25741868): patient phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
No proband phenotype or family history is present in the case records (review_manifest.json, case_summary.json, evidence_brief.json); ClinVar submissions for this variant carry only generic or empty condition labels.
PMID:31285513 places c.203G>A in a cohort of attenuated adenomatous polyposis and describes the trait as genetically heterogeneous, with APC and MUTYH accounting for only 5-10% of AAP and AXIN2, POLE, POLD1, NTHL1 and MSH3 as additional candidate genes.
No AXIN2 CSPEC/VCEP phenotype-specificity specification is available, so generic ACMG/AMP 2015 PP4 applies.
Still missing
No proband phenotype, clinical indication, HPO terms or family history is documented for this case, so phenotype specificity for a single-gene disorder cannot be judged.
No gene-specific PP4 phenotype checklist exists (no AXIN2 ClinGen CSPEC/VCEP available for this case).
BS4Not assessed: no family or non-segregation data exist in any source, and submitters' likely-benign classifications alone cannot establish BS4.
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Reasoning
BS4 (lack of segregation in affected members of a family) requires a family in which affected carriers and affected non-carriers are both observed, showing that the variant does not track with disease (Richards et al. 2015, PMID:25741868). No such family exists in this case: there is no pedigree, no genotyped relative, and therefore no affected non-carrier that could demonstrate non-segregation. PMID:31285513, the only source reporting this variant (c.203G>A, p.Arg68Gln, rs138056036), presents a single unrelated attenuated adenomatous polyposis patient (ID 79) with no relatives analysed, and PMID:28944238, which sequenced AXIN2 in 1231 colorectal cancer cases and 93 controls, never names the variant and performs no family analysis. Two ClinVar submitters classify the variant as likely benign, but BS4 cannot be taken from another source's final classification, and neither submission reports the family-level non-segregation data BS4 requires; the ClinVar record (ClinVarID 127940) as a whole contains no pedigree or segregation information. Because the requisite non-segregation evidence is absent rather than demonstrated, BS4 is recorded as not assessed: this is a data gap, not a benign finding. Generic ACMG/AMP 2015 applies (no ClinGen CSPEC for AXIN2; framework_complete=false).
Evidence considered
BS4 definition applied per Richards et al. 2015 (PMID:25741868): lack of segregation in affected members of a family.
No pedigree, genotyped relative, or affected non-carrier is reported for AXIN2 c.203G>A in the case record or in any reviewed source; searches for 'segregat', 'pedigree', 'family', 'affected', 'proband' and 'meiosis' return no matches.
PMID:31285513 reports the variant once, in a single unrelated adult attenuated adenomatous polyposis patient (ID 79), with no relatives analysed; no non-segregation is described.
PMID:28944238 provides only gene-level AXIN2 commentary from a 1231-case colorectal cancer cohort and never names c.203G>A; no family-level segregation or non-segregation analysis is presented.
The ClinVar record (ClinVarID 127940) contains 9 germline submissions and no pedigree, segregation, or non-segregation data; two submitters report likely benign classifications, but BS4 is not inferred from another source's final classification.
The variant is present in gnomAD v2.1 (37/274598 alleles, 0 homozygotes, total AF 1.35e-4, highest Admixed American AF 2.58e-4) and has been observed in unrelated adult carriers; this is population-frequency evidence relevant to a different criterion group and is not family non-segregation evidence for BS4.
Generic ACMG/AMP 2015 fallback applies: no ClinGen CSPEC is available for AXIN2 and no gene-specific VCEP framework governs this case (framework_complete=false).
Still missing
No family with multiple affected members genotyped for AXIN2 c.203G>A, so non-segregation (affected non-carriers) cannot be demonstrated.
No pedigree or segregation data in any of the 9 ClinVar germline submissions (ClinVarID 127940).
A multi-generation family with both affected carriers and affected non-carriers is required to evaluate BS4; population-level and ClinVar-classification evidence cannot substitute for it.
Not applicable · 4· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/APVS1 (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.
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PM4N/APM4 (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.
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BP3N/ABP3 (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.
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BP7N/ABP7 (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.
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Rule
deterministic_prefilter: requires_synonymous
Evidence considered
Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
Identifiers
Gene
AXIN2
Transcript
NM_004655.4
Coding (HGVS c.)
NM_004655.4:c.203G>A
Protein (HGVS p.)
NP_004646.3:p.(Arg68Gln)
GRCh38
chr17:65558418 C>T
GRCh37
chr17:63554536 C>T
Location and type
Exon 2 · missense
ClinVar
127940
COSMIC
COSV100196332
Gene diagram
Every interpreted variant in AXIN2, mapped onto the exon structure of NM_004655.4. Select a row to find it on the plot.
AXIN2NM_004655.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in AXIN2—Select a row to find it on the plot; use the link to open its page.
AF 0.00013 · 210 / 1,600,510 alleles · 0 hom · FAF 0.00028
Admixed American24 / 59,418
0.0004
European (non-Finnish)174 / 1,171,418
0.00015
Remaining individuals7 / 61,834
0.00011
African/African American3 / 74,742
4e-05
East Asian1 / 44,656
2.2e-05
European (Finnish)1 / 63,580
1.6e-05
0 alternate alleles recorded in 4 other groups: Amish, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00013 · 37 / 274,598 alleles · 0 hom · FAF 0.00016
Admixed American9 / 34,930
0.00026
European (non-Finnish)26 / 125,690
0.00021
East Asian1 / 19,914
5e-05
African/African American1 / 24,932
4e-05
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000131208; MAF= 0.01312%, 210/1600510 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000403918; MAF= 0.04039%, 24/59418 alleles, homozygotes = 0); grpmax FAF= 0.00027822.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000134742; MAF= 0.01347%, 37/274598 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000257658; MAF= 0.02577%, 9/34930 alleles, homozygotes = 0); grpmax FAF= 0.00015724.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Pangolin splice lossmagnitude shown
-0.008
Pangolin splice gain
0.067
Other predictors
REVEL
0.176
BayesDel
-0.262
How the predictions were used
BP4ModerateMet (moderate): REVEL 0.176 for p.(Arg68Gln) is at or below the <= 0.183 moderate BP4 benign threshold.
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Reasoning
BP4 applies to computational evidence suggesting no impact on gene or gene product. NM_004655.4:c.203G>A is a missense substitution (NP_004646.3:p.(Arg68Gln)), so BP4 is taken from the missense protein-impact path, REVEL, and only from that path; the SpliceAI splice path is not applicable to a missense variant and no splice prediction was used, either for or against this criterion. The calibrated REVEL score for this allele (chr17:g.65558418C>T, GRCh38) is 0.176, which satisfies the ClinGen SVI REVEL BP4 moderate cutoff of <= 0.183 and the supporting cutoff of <= 0.29, but not the strong cutoff of <= 0.016 (Pejaver et al. 2022, PMID:36413997). The score clears the moderate cutoff narrowly (0.176 vs 0.183, a margin of 0.007) while clearing the supporting cutoff comfortably, so BP4 is met at moderate strength; the direction of the evidence (benign effect on protein function) is secure either way. Independent clinical-laboratory ClinVar submissions on this exact variant reach the same in silico conclusion for the same tool: St. Jude Molecular Pathology (SCV002584759) states that 'the in silico tool revel predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies', and GeneDx (SCV000149781) states that 'in silico analysis indicates that this missense variant does not alter protein structure/function'. The local BayesDel score (-0.262489) is excluded from this assessment because no generic ACMG-strength BayesDel calibration exists, and it is not needed here. No ClinGen CSPEC specification and no VCEP/gene-specific framework exists for AXIN2 (framework_complete = false), so the generic ACMG/AMP 2015 BP4 criterion with the published REVEL calibration applies. BP4 is met, strength moderate.
Rule
missense -> REVEL path; BP4 met at moderate because REVEL 0.176 <= 0.183 (and <= 0.29 supporting), but > 0.016 strong (Pejaver et al. 2022, PMID:36413997)
Evidence considered
Consequence class: missense (NP_004646.3:p.(Arg68Gln)) - BP4 taken from the REVEL missense path only, not from SpliceAI; the two paths are never combined and no prediction is double-counted.
REVEL v1.3 local lookup (revel block): score 0.176 for chr17:g.65558418C>T (GRCh38), the same allele as NC_000017.10:g.63554536C>T.
Thresholds applied: BP4 supporting requires REVEL <= 0.29; moderate <= 0.183; strong <= 0.016 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, Am J Hum Genet, PMID:36413997). 0.176 meets supporting and moderate but not strong.
Concordant ClinVar submitter in silico statements for the exact variant: SCV002584759 (St. Jude Molecular Pathology) - REVEL predicts a benign effect on protein function; SCV000149781 (GeneDx) - in silico analysis indicates this missense variant does not alter protein structure/function.
BayesDel (-0.262489) excluded: no generic ACMG-strength calibration is established, so it is treated as not_available for PP3/BP4 rather than as an additional benign predictor.
SpliceAI returned no score for this variant (query timeout; max_delta_score null, Pangolin SG 0.067/SL -0.008 only) and the uncalibrated Pangolin output was not used; being a missense variant, the splice path is out of scope for BP4 here.
No ClinGen CSPEC record and no VCEP/gene-specific PP3-BP4 lookup material exists for AXIN2, so no gene-specific pre-assigned code overrides the generic thresholds.
Still missing
The REVEL score (0.176) clears the moderate BP4 cutoff (<= 0.183) by only 0.007, so the moderate-vs-supporting strength grade is borderline; the criterion itself is met at no less than supporting strength.
PP3Not met: REVEL 0.176 for p.(Arg68Gln) sits far below the >= 0.644 supporting PP3 threshold.
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Reasoning
PP3 requires computational evidence that supports a deleterious effect on the gene or gene product. NM_004655.4:c.203G>A is a missense substitution predicted to produce NP_004646.3:p.(Arg68Gln) (consequence_class = missense), so the applicable predictor path for PP3/BP4 is the missense protein-impact path, REVEL; the SpliceAI splice path is not applicable to a missense variant and was therefore not consulted, and SpliceAI's absent score was not used in either direction. The calibrated REVEL score for this change (chr17:g.65558418C>T, GRCh38, = NC_000017.10:g.63554536C>T) is 0.176, which is below the ClinGen SVI REVEL supporting PP3 cutoff of >= 0.644 (Pejaver et al. 2022, PMID:36413997) and therefore also below the moderate (>= 0.773) and strong (>= 0.932) cutoffs. The local BayesDel score (-0.262489) is present but no generic ACMG-strength BayesDel calibration is established, so it is treated as not available for PP3 rather than being counted as additional support. No ClinGen CSPEC specification and no VCEP/gene-specific framework exists for AXIN2 (framework_complete = false; fallback = generic ACMG/AMP 2015), so the generic thresholds apply without any gene-specific override. PP3 is therefore not met.
Rule
missense -> REVEL path; PP3 not met because REVEL 0.176 < 0.644 supporting cutoff (Pejaver et al. 2022, PMID:36413997)
Evidence considered
Consequence class: missense (NP_004646.3:p.(Arg68Gln)) - selects the REVEL missense path for PP3/BP4; the SpliceAI splice path is out of scope for this variant class.
REVEL v1.3 local lookup (revel block): score 0.176 for chr17:g.65558418C>T (GRCh38), i.e. the same allele as NC_000017.10:g.63554536C>T.
Threshold applied: PP3 supporting requires REVEL >= 0.644; moderate >= 0.773; strong >= 0.932 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, Am J Hum Genet, PMID:36413997). 0.176 falls below all three, so PP3 is not met.
BayesDel (-0.262489, local BayesDel_170824_noAF lookup) was noted but excluded: no generic ACMG-strength BayesDel calibration is established, so per instruction it is treated as not_available for PP3/BP4 and cannot support PP3.
SpliceAI returned no score for this variant (query timeout, max_delta_score null, Pangolin only); this is missing data and, being a missense variant, the splice path was never the applicable path - it was not used to support or refute PP3.
No ClinGen CSPEC record and no VCEP/gene-specific PP3-BP4 lookup material exists for AXIN2; generic ACMG/AMP 2015 with the published calibration thresholds governs.
BP7N/ABP7 (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.
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Rule
deterministic_prefilter: requires_synonymous
Evidence considered
Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
Statement
In silico
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.176. BayesDel score = -0.262489.
7 paper records listed. 1 cited in the classification.
Cited in the classification
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Richards S et al. · 2015 May
The ACMG/AMP 2015 joint consensus standards-and-guidelines document (Richards et al.) that defines the five-tier terminology and the pathogenic/benign evidence criteria (PVS1, PS1-4, PM1-6, PP1-5, BA1, BS1-4, BP1-6) and combination rules. It contains no gene-specific or variant-specific data: AXIN2 is never named and neither c.203G>A nor p.(Arg68Gln) appears. Its relevance is framework-level, including the statement that the classification approach applies to variants in all Mendelian genes regardless of testing modality.
→ BP1 · supporting→ BP4 · moderateDoes not name this variant
The variant classification approach described in this article is meant to be applicable to variants in all Mendelian genes, whether identified by single gene tests, multigene panels, exome sequencing, or genome sequencing.
Location Methods, final paragraph (framework statement); gene and variant are not mentioned anywhere in the paper
Context Consensus guideline document: workgroup surveys of >100 sequencing laboratories, an open forum at the 2013 ACMG annual meeting, a November 2013 AMP workshop, and review of existing society guidelines. No cohort, assay, or functional data generated.
Other recorded publications
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
Karbassi I et al. · 2016
A methodology report describing a rules-based, weighted variant pathogenicity scoring system applied to 16,500+ assessments across 338 genes (neurological, endocrine, and nephrotic disorders). It contains no mention of AXIN2 or of the c.203G>A (p.R68Q) variant, and provides no functional, case, segregation, or population data for either. Its relevance is method-level only: it describes how missense variants are scored using prediction tools, minor evidence categories such as conserved/functional domains and known pathogenic variants at the same residue, population frequency, co-occurrence, segregation, and published functional studies.
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.
Maxwell KN et al. · 2016
Neither the AXIN2 gene nor the variant c.203G>A (p.R68Q) is named anywhere in this paper. The study reports whole-exome sequencing and ACMG/AMP-based classification of 1,640 non-silent germline variants across 180 medically relevant genes in 404 individuals from 253 breast/ovarian cancer-prone families, but AXIN2 is not among the genes discussed in the narrative text and no variant-specific data, functional assay, segregation, case observation, or population frequency for p.(R68Q) is presented.
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.
DeRycke MS et al. · 2017
Targeted custom-capture sequencing of 36 known/suspected colorectal cancer susceptibility genes, including AXIN2 (NM_004655.3), in 1231 CRC cases and 93 unaffected controls. AXIN2 carried no Tier 1 (truncating) variants and was among the genes with only a single Tier 1-or-predicted-damaging Tier 2 variant across the cohort. The only AXIN2 variant named in the paper is the in-frame indel p.His474_Ser475insHis, present in three cases. The variant of interest, AXIN2 c.203G>A (p.Arg68Gln), is not named by coding or protein notation; only gene-level AXIN2 commentary is provided.
while a single Tier 1 or damaging Tier 2 variant was detected in AXIN2, CDKN1B, CDKN2A, and SMAD2.
Discussion, paragraph 5 (gene-level summary); also Results, Tier 2 variants and Table 4 (AXIN2 among genes with one predicted damaging variant), and Table S3 (AXIN2 p.His474_Ser475insHis indel)
Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing.
Lorca V et al. · 2019
The AXIN2 variant c.203G>A p.(Arg68Gln) (rs138056036) was detected in one attenuated adenomatous polyposis patient (ID 79) in a Spanish cohort of 158 AAP subjects screened by a multigene NGS panel. It was heterozygous, had a gnomAD (European Non-Finnish) frequency of 2e-04, was annotated to the SMART protein domain AXIN1_TNKS, and was classified as class 3, i.e. a variant of uncertain significance under ACMG-SHERLOC criteria. It was not among the actionable findings; the paper states that none of the patients showed actionable (class-4/class-5) mutations in AXIN2. No functional, segregation, or somatic data specific to this variant are presented.
79 c.203G > A p.(Arg68Gln) rs138056036 2e-04 AXIN1_TNKS 3
Table 2 (validated variants and classification according to ACMG-SHERLOC criteria), AXIN2 rows, patient ID 79; corroborated in Results (germline DNA screening) and Discussion ('None of the patients showed actionable mutations (class-4 and -5) in any of the genes associated with new polyposis syndromes (MSH3, NTHL1, POLD1, POLE or AXIN2)')
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
Hampel H et al. · 2015
This paper (Hampel et al., ACMG/NSGC practice guideline, Genet Med 2015;17(1):70-77) is a clinical referral guideline that lists personal and family history criteria warranting referral for cancer genetic consultation across hereditary cancer syndromes (HBOC, Lynch syndrome, FAP/MAP, Cowden, Li-Fraumeni, Birt-Hogg-Dube, Carney complex, MEN1/2, etc.). It contains no mention of AXIN2, and no mention of the c.203G>A (p.R68Q) variant. The guideline reports no functional assay, case observation, segregation, or population-frequency data for AXIN2; colorectal cancer referral criteria in the tables are tied to LS, CMMRD, MAP, FAP, Cowden and Li-Fraumeni syndromes, none of which are attributed to AXIN2. No variant-specific or gene-specific evidence relevant to AXIN2 c.203G>A can be extracted from this text.
Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.
Chrysafi P et al. · 2023
ClinVar-cited source with no full text retrieved and no full-text extraction performed, so only its abstract could be screened. It is a retrospective observational study of the prevalence of pathogenic mutations and variants of uncertain significance in patients undergoing genetic testing for hereditary breast and ovarian cancer and Lynch syndrome. The abstract makes no mention of AXIN2 and no mention of the c.203G>A (p.R68Q) variant, and it reports no proband-level, parental, pedigree, co-segregation, or non-segregation data relevant to this group; no de novo or family data for this variant can be drawn from it.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000131208; MAF= 0.01312%, 210/1600510 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000403918; MAF= 0.04039%, 24/59418 alleles, homozygotes = 0); grpmax FAF= 0.00027822.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000134742; MAF= 0.01347%, 37/274598 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000257658; MAF= 0.02577%, 9/34930 alleles, homozygotes = 0); grpmax FAF= 0.00015724.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 127940)
In silico
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.176. BayesDel score = -0.262489.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AXIN2, a tumor suppressor involved in WNT signaling, is mutated at low frequencies in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100196332, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
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