AXIN2 c.2051C>T, p.(Ala684Val)

Reasoning

No applicable AXIN2-specific VCEP framework was retrieved, so generic ACMG/AMP PP4 applies. The exact variant c.2051C>T (p.Ala684Val) was reported in a male proband with isolated oligodontia who was missing 10 teeth; the source defines oligodontia as congenital absence of at least six permanent teeth and describes it as a heritable condition associated with AXIN2. This is a disease-relevant and relatively specific phenotype for the AXIN2 oligodontia presentation, supporting PP4 at supporting strength. A separate CRC-panel report identified the same variant in a patient without oligodontia, so the phenotype evidence is not sufficiently uniform for greater strength.

Rule

generic_acmg_amp: disease_specific_or_highly_specific_patient_phenotype_supports_PP4

Evidence considered

• PMID:21626677 reports the exact variant in a male with isolated oligodontia and 10 absent teeth, and describes oligodontia as a heritable condition associated with AXIN2.
• PMID:27696107 reports the exact variant in a colorectal-cancer-panel patient and states that oligodontia was not present in any study patient; this limits phenotype uniformity but does not negate the documented AXIN2 oligodontia presentation.

Sources

Reasoning

The variant is a missense substitution, NM_004655.4:c.2051C>T (p.Ala684Val), so the missense REVEL path applies and SpliceAI is not considered. REVEL is 0.157, meeting the generic calibrated BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore BP4 is met at supporting strength. BayesDel is not used because no generic ACMG strength calibration is established.

Rule

Generic ClinGen SVI REVEL calibration: BP4 supporting at REVEL <=0.29; missense variants use REVEL only.

Evidence considered

• The variant is an exonic missense substitution, NM_004655.4:c.2051C>T (p.Ala684Val), establishing REVEL as the sole applicable PP3/BP4 path.
• Local REVEL lookup reports a score of 0.157, meeting the generic BP4 supporting cutoff of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
• SpliceAI was not used because a missense variant must be evaluated through the REVEL path only; BayesDel was not used because no generic ACMG-strength calibration is established.

Sources

Reasoning

PS1 is not met. The reviewed literature reports the queried AXIN2 c.2051C>T (p.Ala684Val) variant itself, including in PMID:21626677, PMID:24581859, and PMID:27696107, but no reviewed source documents a different nucleotide change producing the same p.Ala684Val substitution. Reports of the same nucleotide variant do not satisfy PS1.

Rule

PS1 requires a well-established different nucleotide change resulting in the same amino-acid change.

Evidence considered

• PMID:21626677 reports AXIN2 c.2051C>T p.Ala684Val in a proband with isolated oligodontia.
• PMID:24581859 cites c.2051C>T as a previously reported AXIN2 mutation but does not identify an alternate nucleotide change causing p.Ala684Val.
• PMID:27696107 reports c.2051C>T p.Ala684Val in patient I:11; this is the same nucleotide variant, not an independent codon change producing the same amino-acid substitution.

Sources

Reasoning

PM2 is not met. Under the generic SVI recommendation supplied for this case, PM2 supporting requires AF <=0.0001. The default all-comers gnomAD v4.1 AF is 0.00170591, with maximum population AF 0.00888994; gnomAD v2.1 reports AF 0.00155875, and its maximum population AF is 0.00854113. The specifically available gnomAD v2.1 non-cancer exome subset still reports AF 0.00158494, so using that older exome-only subset does not rescue PM2. The variant is therefore substantially more frequent than the PM2 threshold.

Rule

Generic SVI PM2 supporting: allele frequency <=0.0001; no applicable AXIN2-specific VCEP specification identified.

Evidence considered

• gnomAD v4.1 reports 2753/1613800 alleles, overall AF 0.00170591, and maximum population AF 0.00888994.
• gnomAD v2.1 reports overall AF 0.00155875, and its non-cancer exome-only subset reports AF 0.00158494 (367/231554 alleles).
• The supplied generic SVI PM2 supporting threshold is AF <=0.0001 (ClinGen SVI recommendation associated with PMID:25741868).

Sources

Reasoning

PM5 is not met. The reviewed sources document AXIN2 p.Ala684Val, but no alternate missense substitution at residue 684 with established pathogenic or likely pathogenic evidence was identified. The available reports of the queried variant itself cannot serve as PM5 comparator evidence, and ClinVar submissions for the same variant do not establish an independent alternate-residue pathogenic comparator.

Rule

PM5 requires a different missense change at the same amino-acid residue that is established as pathogenic or likely pathogenic.

Evidence considered

• PMID:21626677 reports p.Ala684Val, the queried variant, rather than an alternate missense change at residue 684.
• PMID:24581859 discusses c.2051C>T as a previously reported AXIN2 mutation and does not provide a pathogenic alternate substitution at residue 684.
• PMID:27696107 reports p.Ala684Val, the queried variant, and does not provide an alternate pathogenic residue-684 variant.
• ClinVar contains submissions for the queried p.Ala684Val variant but does not provide an independent established pathogenic alternate missense comparator at residue 684.

Sources

Reasoning

The variant is a missense substitution, NM_004655.4:c.2051C>T (p.Ala684Val), so the missense REVEL path applies and SpliceAI is not considered. REVEL is 0.157, which is below the generic calibrated PP3 supporting threshold of >=0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore PP3 is not met. BayesDel is not used because no generic ACMG strength calibration is established.

Rule

Generic ClinGen SVI REVEL calibration: PP3 supporting at REVEL >=0.644; missense variants use REVEL only.

Evidence considered

• The variant is an exonic missense substitution, NM_004655.4:c.2051C>T (p.Ala684Val), establishing REVEL as the sole applicable PP3/BP4 path.
• Local REVEL lookup reports a score of 0.157, below the generic PP3 supporting cutoff of >=0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
• SpliceAI was not used because a missense variant must be evaluated through the REVEL path only; BayesDel was not used because no generic ACMG-strength calibration is established.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 127941 has exact-variant submissions, but the audit reports zero expert-panel submissions; the available classifications are ordinary laboratory or other non-expert assertions, including Likely benign and Benign. Therefore PP5 is not met, regardless of the aggregate ClinVar label or literature attached to individual submissions.

Rule

exact_variant_clinvar_expert_panel_pathogenic_or_likely_pathogenic_only

Evidence considered

• ClinVar variation 127941 exactly matches NM_004655.4(AXIN2):c.2051C>T (p.Ala684Val).
• The ClinVar submission audit reports expert_panel_submissions: 0; no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions were excluded from PP5 by the governing criterion rule.

Sources

Reasoning

BA1 is not met. Under the generic ACMG/AMP fallback, the stand-alone benign threshold is allele frequency >=0.05. The default all-comers gnomAD sources are applicable because no AXIN2-specific VCEP framework was found: gnomAD v4.1 reports an overall AF of 0.00170591 (2753/1613800 alleles), and its highest population AF is 0.00888994 in Ashkenazi Jewish individuals (263/29584 alleles), both far below 0.05. The gnomAD v2.1 non-cancer exome AF is also only 0.00158494, but no governing specification requires that subset here.

Rule

Generic ACMG/AMP BA1: allele frequency >=0.05; no applicable AXIN2-specific VCEP specification identified.

Evidence considered

• gnomAD v4.1 reports 2753/1613800 alleles, overall AF 0.00170591, and the highest population AF is 0.00888994 in the Ashkenazi Jewish population.
• The generic ACMG/AMP stand-alone benign population-frequency threshold is AF >=0.05 (PMID:25741868).
• The available gnomAD v2.1 non-cancer exome subset reports AF 0.00158494 (367/231554 alleles), which also does not approach the BA1 threshold; no AXIN2-specific VCEP requires this subset.

Sources

Reasoning

BS1 is not met. Under the generic ACMG/AMP fallback, the supplied strong benign threshold is AF >=0.01. The default all-comers gnomAD v4.1 overall AF is 0.00170591 and its highest reported population AF is 0.00888994 in Ashkenazi Jewish individuals, both below 0.01. gnomAD v2.1 likewise reports an overall AF of 0.00155875 and highest population AF of 0.00854113. The gnomAD-Canada Ashkenazi Jewish estimate is 0.0108173, but it is based on only 9 alternate alleles among 832 alleles in that small subset and does not supersede the large gnomAD population estimates absent a governing specification.

Rule

Generic SVI BS1: allele frequency >=0.01; no applicable AXIN2-specific VCEP specification identified.

Evidence considered

• gnomAD v4.1 reports overall AF 0.00170591 and maximum population AF 0.00888994 in Ashkenazi Jewish individuals; gnomAD v2.1 reports overall AF 0.00155875 and maximum population AF 0.00854113.
• The generic SVI strong benign threshold supplied for BS1 is AF >=0.01 (Whiffin et al., PMID:28518168).
• gnomAD-Canada reports 9/832 alleles in its Ashkenazi Jewish subset (AF 0.0108173), but this small-subset estimate is not adopted as the governing frequency for BS1 because no AXIN2-specific specification requires it and the larger gnomAD datasets remain below threshold.

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 127941 has exact-variant submissions, but the audit reports zero expert-panel submissions; the available Benign and Likely benign classifications are ordinary laboratory or other non-expert assertions. Therefore BP6 is not met, and neither the aggregate ClinVar label nor single-submitter classifications can trigger it.

Rule

exact_variant_clinvar_expert_panel_benign_or_likely_benign_only

Evidence considered

• ClinVar variation 127941 exactly matches NM_004655.4(AXIN2):c.2051C>T (p.Ala684Val).
• The ClinVar submission audit reports expert_panel_submissions: 0; available Benign and Likely benign assertions are from non-expert submissions.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions were excluded from BP6 by the governing criterion rule.

Sources

Reasoning

PS2 cannot be assessed. PMID:21626677 reports NM_004655.4:c.2051C>T (p.Ala684Val) in one male proband with isolated oligodontia, and PMID:27696107 reports the same variant in patient I:11, but neither source documents confirmed parental testing showing the variant absent in both parents. The available evidence therefore does not establish a de novo origin, and no independent parental-genotype or maternity/paternity evidence is provided.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in the patient with confirmed maternity and paternity; no applicable AXIN2-specific specification was available.

Evidence considered

• PMID:21626677 reports c.2051C>T (p.Ala684Val) in a male proband with isolated oligodontia and 10 missing teeth, but provides no documented parental testing for this variant.
• PMID:27696107 reports c.2051C>T (p.Ala684Val) in patient I:11 and confirms the finding by Sanger sequencing, but provides no documented parental testing or de novo determination.

Still missing

• Confirmed parental genotypes for the reported proband(s), including testing of both biological parents
• Evidence excluding maternity/paternity or other sample-identity concerns if a de novo claim is made

Sources

Reasoning

No applicable AXIN2-specific VCEP specification was available, so generic ACMG/AMP functional-evidence guidance was used. The reviewed variant-specific publications report identification of NM_004655.4:c.2051C>T (NP_004646.3:p.(Ala684Val)) in clinical cohorts and describe population or computational observations, but they do not report a validated functional assay of the variant, assay controls, or a biologically relevant loss-of-function result. Therefore, PS3 cannot be applied.

Rule

Generic ACMG/AMP PS3 requires well-established functional studies showing a damaging effect; no qualifying assay evidence was identified.

Evidence considered

• PMID:21626677 reports the exact variant in a Swedish oligodontia cohort and evaluates computational predictions and controls, but provides no variant-specific functional assay.
• PMID:24581859 cites the exact c.2051C>T variant in a prior oligodontia study but provides no functional assay data for it.
• PMID:27696107 reports the exact variant in a colorectal-cancer panel study with frequency and in-silico results, but no functional assay or experimental activity measurement.

Still missing

• A validated, biologically relevant functional assay directly testing AXIN2 c.2051C>T (p.Ala684Val), with appropriate positive and negative controls, is unavailable.

Sources

Reasoning

No applicable AXIN2-specific VCEP framework was retrieved, so the generic ACMG/AMP PS4 concept applies: a significantly increased prevalence of the exact variant in affected individuals compared with appropriate controls. The literature documents NM_004655.4:c.2051C>T (p.Ala684Val) in one oligodontia proband from a cohort of 93 affected individuals and reports absence from 200 Swedish control chromosomes, but it does not provide a case-control enrichment statistic, confidence interval, or a sufficiently characterized exact-variant case series to establish PS4. The reported observation is therefore insufficient for a PS4 call.

Rule

generic_acmg_amp: requires_significantly_increased_variant_prevalence_in_affected_cases_vs_controls

Evidence considered

• PMID:21626677 reports AXIN2 c.2051C>T (p.Ala684Val) in one male proband with isolated oligodontia among 93 Swedish individuals and states that the variant was absent from 200 Swedish control chromosomes.
• PMID:24581859 repeats that c.2051C>T was identified among two AXIN2 mutations in 93 individuals with non-syndromic oligodontia, without providing an exact-variant enrichment statistic.
• The generic PS4 requirement is affected-case enrichment relative to appropriate controls; no odds ratio, confidence interval, or validated threshold was available for this exact variant.

Still missing

• A validated exact-variant case-control enrichment analysis or sufficiently characterized affected-case series is needed for PS4.

Sources

Reasoning

PM1 could not be established from the available evidence. No applicable AXIN2 VCEP or gene-specific framework was retrieved, vcep_materials.json has no AXIN2 domain_tables entry, and the hotspot source reports no statistically significant hotspot for AXIN2 A684. No independently validated critical functional domain encompassing residue 684 was supplied, so PM1 cannot be met using generic evidence alone.

Rule

PM1 requires a variant to lie in a well-established critical functional domain or hotspot without benign variation; a VCEP specification takes precedence when available.

Evidence considered

• vcep_materials.json reports no applicable AXIN2 VCEP materials and an empty domain_tables object; therefore there is no authoritative gene-specific domain list to apply.
• The Cancer Hotspots result for AXIN2 A684 states that the variant does not lie in a statistically significant hotspot.
• No reviewed source supplied a validated critical functional domain boundary that includes AXIN2 residue 684.

Still missing

• A validated AXIN2 critical-functional-domain annotation covering residue 684 is unavailable.
• No applicable AXIN2 VCEP specification was retrieved.

Sources

Reasoning

PM6 cannot be assessed. The literature identifies the variant in individual patients, including a male oligodontia proband in PMID:21626677 and patient I:11 in PMID:27696107, but neither report states that the variant was presumed de novo without parental testing. No case-level report supplies a de novo inference, and no parental genotypes or maternity/paternity information are available.

Rule

Generic ACMG/AMP PM6 applies to a presumed de novo variant when parental testing is unavailable; the available reports do not make that presumption for this variant.

Evidence considered

• PMID:21626677 describes the variant in one affected proband but does not report a presumed de novo origin.
• PMID:27696107 describes the variant in patient I:11 but does not report a presumed de novo origin or parental testing.

Still missing

• A case report explicitly stating presumed de novo inheritance
• Available parental testing or a documented basis for presuming de novo status

Sources

Reasoning

PP1 cannot be assessed. PMID:21626677 reports the variant in one oligodontia proband, and PMID:24581859 cites that prior report, but the extracted evidence does not provide affected relatives carrying the variant, unaffected relatives tested for absence, a pedigree, or a count of informative meioses. PMID:27696107 reports the variant in a single patient without segregation analysis. A single patient observation is not cosegregation evidence.

Rule

Generic ACMG/AMP PP1 requires cosegregation with disease in affected family members; no applicable AXIN2-specific specification was available.

Evidence considered

• PMID:21626677 reports the variant in a male proband with isolated oligodontia but does not provide family segregation data.
• PMID:24581859 cites the prior identification of c.2051C>T among 93 individuals with non-syndromic oligodontia, but does not add individual-level segregation or pedigree data for this variant.
• PMID:27696107 reports the variant in patient I:11 but does not provide segregation analysis or informative meioses.

Still missing

• Pedigree-level data with phenotype status and variant genotypes for relatives
• Number of informative meioses and affected relatives carrying the variant
• Testing results for relevant unaffected relatives

Sources

Reasoning

PP2 was not assessed as met because no validated AXIN2-specific missense mechanism demonstrates that pathogenic missense variation is common while benign missense variation is rare. The available gene-level material describes AXIN2 biology and reports both truncating and missense variants, but does not provide a sufficiently established gene-wide missense-enrichment framework for applying PP2.

Rule

PP2 requires that missense variants are a common disease mechanism in the gene and that benign missense variation is uncommon.

Evidence considered

• The AXIN2 gene context describes tumor-suppressor and Wnt-signaling biology but does not establish the missense-variant distribution required for PP2.
• PMID:21626677 reports AXIN2 missense variants in oligodontia but does not establish a gene-wide pathogenic-missense enrichment pattern.
• PMID:27696107 discusses truncating versus missense AXIN2 variants but does not provide a validated PP2 gene-specific framework.

Still missing

• A validated AXIN2-specific missense-enrichment or missense-mechanism assessment is unavailable.

Sources

Reasoning

BS2 cannot be established from the available population data. gnomAD v4.1 reports six homozygotes overall, including six in the non-Finnish European population, while gnomAD v2.1 and the available v2.1 non-cancer exome subset report zero homozygotes. However, the records do not establish that the six individuals are healthy adults phenotyped for AXIN2-related oligodontia or cancer risk, and AXIN2-related cancer predisposition has age-dependent and incomplete penetrance considerations. Therefore, the homozygote count is potentially informative but is not sufficient to apply BS2 without phenotype and ascertainment confirmation.

Rule

Generic ACMG/AMP BS2 requires observation in healthy individuals appropriate to the disorder and penetrance; population homozygote counts without phenotype ascertainment are insufficient here.

Evidence considered

• gnomAD v4.1 reports total_hom 6, with six homozygotes in the non-Finnish European population; the maximum Ashkenazi Jewish population also has zero homozygotes.
• gnomAD v2.1 reports zero homozygotes overall, and the gnomAD v2.1 non-cancer exome subset also reports zero homozygotes.
• The generic BS2 concept requires observation in appropriately healthy individuals, but the supplied records do not provide individual-level health, age, or phenotype ascertainment for the gnomAD v4.1 homozygotes.

Still missing

• No individual-level phenotype, age, health-status, or ascertainment information is available for the six gnomAD v4.1 homozygotes.
• The relationship between homozygosity for p.Ala684Val and AXIN2-related oligodontia or cancer-risk penetrance is not established by the supplied population records.

Sources

Reasoning

No applicable AXIN2-specific VCEP specification was available, so generic ACMG/AMP functional-evidence guidance was used. The reviewed variant-specific publications do not report a validated functional assay showing that NM_004655.4:c.2051C>T (NP_004646.3:p.(Ala684Val)) has normal function, nor do they provide assay controls or a biologically relevant normal-activity result. The available computational, population, and clinical observations cannot substitute for BS3 functional evidence. Therefore, BS3 cannot be applied.

Rule

Generic ACMG/AMP BS3 requires well-established functional studies showing no damaging effect; no qualifying assay evidence was identified.

Evidence considered

• PMID:21626677 reports the exact variant and computational conservation or prediction findings, but no validated normal-function assay.
• PMID:24581859 mentions the exact variant through prior clinical literature and supplies no functional assay result.
• PMID:27696107 reports the exact variant with population and in-silico data, but no assay demonstrating preserved biological function.

Still missing

• A validated, biologically relevant functional assay directly demonstrating normal AXIN2 function for c.2051C>T (p.Ala684Val), with appropriate positive and negative controls, is unavailable.

Sources

Reasoning

BS4 cannot be assessed. The available reports do not document clinically informative unaffected relatives who were tested and found to carry the variant, nor do they provide non-segregation across a pedigree. The presence of the variant in population databases or in isolated patients does not establish non-segregation with disease, and no affected-family comparison is reported for this variant.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected members of a family; no applicable AXIN2-specific specification was available.

Evidence considered

• PMID:21626677 provides a proband-level report and control-chromosome comparison, but no unaffected relatives tested for the familial variant.
• PMID:27696107 provides a patient-level report and does not document relatives, phenotype-matched testing, or non-segregation.

Still missing

• Phenotypically informative unaffected relatives tested for the variant
• Pedigree-level evidence showing the variant does not track with disease

Sources

Reasoning

BP1 was not assessed as met because the available evidence does not establish the required AXIN2-specific pattern that truncating variants cause disease while missense variants are a less common disease mechanism. The gene context and PMID:27696107 discuss truncating variants and suggest missense variants may be less associated with colorectal cancer, but this is not a validated gene-specific BP1 rule and the source itself describes the comparison as suggestive rather than definitive.

Rule

BP1 requires a missense variant in a gene where truncating variants cause disease and missense variants are a less common disease mechanism.

Evidence considered

• The AXIN2 gene context states that truncating mutations have been associated with colorectal cancer but notes that their proposed activity requires further study; it does not establish the BP1 mechanism rule.
• PMID:27696107 states that truncating AXIN2 variants are suggested to be more likely to predispose to syndromic oligodontia and colorectal cancer than missense variants, but this is a discussion-level observation rather than a validated gene-wide BP1 specification.

Still missing

• A validated AXIN2-specific loss-of-function versus missense mechanism assessment is unavailable.

Sources

Reasoning

No AXIN2-specific VCEP specification was retrieved, so the generic ACMG/AMP framework applies. BP2 requires documented co-occurrence and phase: the variant in cis with a pathogenic or likely pathogenic variant, or in trans with a pathogenic or likely pathogenic variant in a disorder for which that configuration supports a benign interpretation. The available reports mention c.2051C>T (p.Ala684Val) in clinical cohorts but do not identify another variant in the same individual, establish cis/trans phase, or provide a qualifying co-occurrence observation. BP2 therefore cannot be assessed from the available evidence.

Evidence considered

• PMID:21626677 reports the target variant in an oligodontia proband but gives no qualifying second variant or phase information.
• PMID:27696107 reports the target variant in colorectal-cancer panel patient I:11 but gives no qualifying second variant or phase information.
• Generic BP2 requires documented qualifying co-occurrence with phase; neither cis nor trans phase is reported for c.2051C>T in the available evidence.

Still missing

• No co-occurring pathogenic or likely pathogenic AXIN2 variant was identified for an individual carrying c.2051C>T.
• No cis/trans phase information is available for a qualifying co-occurring variant.

Sources

Reasoning

No applicable AXIN2-specific VCEP specification was retrieved. The available case evidence does not document a fully characterized affected individual carrying this variant together with a separate pathogenic variant that explains the relevant phenotype, and no governing BP5 likelihood-ratio threshold or other BP5-specific rule was available. The criterion therefore cannot be assessed from the supplied evidence.

Rule

generic_acmg_amp: requires_another_pathogenic_variant_explaining_the_phenotype

Evidence considered

• No qualifying BP5 co-occurrence evidence was identified in the case evidence.
• No AXIN2-specific BP5 rule or likelihood-ratio threshold was available; no numeric BP5 comparison was therefore performed.

Still missing

• A fully characterized co-occurrence case with an independently established pathogenic variant and phenotype attribution is needed for BP5.

Sources