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This variantScenario
BenignPathogenic
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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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
BS3Supporting
BS3 · supporting
Met at supporting strength: RT-PCR of the carrier's RNA showed c.1530G>A present in the same proportion as genomic DNA, indicating no splicing alteration.
BP7Supporting
BP7 · supporting
Met, supporting: synonymous p.(Thr510=) with SpliceAI max delta 0.001, far below the 0.2 significant-impact cutoff.
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
7,188 / 1,613,744 alleles
gnomAD v4.1: 7,188 / 1,613,744 alleles. Recorded AF 0.00445424. Recorded homozygote count 21.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00285292; MAF= 0.28529%, 806/282518 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00489261; MAF= 0.48926%, 631/128970 alleles, homozygotes = 2); grpmax FAF= 0.0047191.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0033739660426643447, 62/18376 alleles, homozygotes = 0).
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 15 not met · 1 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No source reports NM_004655.4:c.1530G>A (p.Thr510=) as a de novo event, and the only study that detected the variant in a patient states that parental DNA samples were unavailable, so a de novo origin has never been tested for this variant.
The variant has been reported only in isolated, unrelated carriers - one 18-year-old with 30 adenomatous polyps and no family history, one of 37 Tunisian tooth-agenesis patients, and one eastern Slovak hypodontia patient - none of whom had relatives genotyped or meiosis data reported.
With no trio testing, no co-segregation analysis and no non-segregation observation available, PS2, PM6, PP1 and BS4 are all not met; family-based evidence contributes nothing to this variant's classification in either direction.
Governing specification: no ClinGen VCEP or CSPEC exists for AXIN2 (no gene-specific framework or rules payload was retrievable for this case), so PS3/BS3 were evaluated under generic ACMG/AMP 2015 with the published generic calibration defaults.
PS3 not met: no functional study shows a damaging effect. The only experimental data on this variant is a negative RNA splicing assay (PMID:16941501), and the change is synonymous (p.Thr510=), leaving no mechanism through which a damaging effect could be demonstrated or expected.
BS3 met at supporting strength: a patient-derived RT-PCR assay documented that c.1530G>A is present in transcript at the same proportion as genomic DNA with no splicing alteration, and the encoded protein is unchanged; strength was capped at supporting because the assay lacks reported controls, replicates, quantitative readout and independent replication, and was performed in a single carrier with the change in cis with c.1235A>G.
The negative functional result is concordant with independent in-silico splice prediction (SpliceAI max delta 0.001) and with the two other cohort papers reporting this codon-510 synonymous change without any assigned pathogenic functional role (PMID:29114927, PMID:30555066).
No ClinGen CSPEC/VCEP and no local gene-specific framework exists for AXIN2, so all five criteria in this group were adjudicated against the generic ACMG/AMP 2015 definitions (framework_complete=false; generic_acmg_fallback).
PS4 not met: the exact variant appears only as isolated single-carrier observations (1/37 non-syndromic tooth agenesis, 1/60 non-syndromic hypodontia, 1/31 polyposis/colorectal cancer) with no odds ratio, relative risk or significant case-control enrichment, and its gnomAD frequency (0.445% v4.1, 21 homozygotes) is inconsistent with a strong case effect at those cohort sizes; no numeric PS4 threshold exists in any governing specification for this gene.
PP4 not assessed: the case is a variant-only submission with no proband phenotype, HPO terms or family history, and the only phenotypes linked to this change in the literature span two unrelated domains (tooth agenesis/hypodontia and colorectal polyposis).
PP5 and BP6 not met: the exact-variant ClinVar record (VCV000136481) has 19 ordinary clinical-laboratory submissions and zero expert-panel submissions, so neither the aggregate Benign/Likely benign label nor any submitter assertion can trigger these criteria under this group's expert-panel-only rule.
BP5 not met: no alternate molecular basis is documented for the proband, and the reported carrier of this variant was APC-negative, MMR-negative and not MUTYH-mutated, with the authors calling the AXIN2 changes likely polymorphisms.
No ClinGen CSPEC/VCEP or local AXIN2 gene-specific framework exists for this case (cspec.found=false; vcep_materials.json: no CSPEC URL, source=generic_acmg_fallback, framework_complete=false), so PM3 and BP2 were adjudicated under generic ACMG/AMP 2015 using the definitions in PMID:25741868.
Both allelic criteria require a pathogenic (or likely pathogenic) AXIN2 partner variant: PM3 for detection in trans with a pathogenic variant, and BP2 for observation in trans (fully penetrant dominant disorder) or in cis with a pathogenic variant. No such partner variant exists in any case source, so neither criterion is met and the allelic group contributes no pathogenic or benign evidence to the final classification.
The only phase-resolved observation of this variant is in cis with a change the authors concluded is 'likely a polymorphism' (PMID:16941501, Table 2: c.[1235A>G (+) 1530G>A]), so the cis observation cannot be converted into BP2; the affected proband carrying it (18 years, 30 adenomatous polyps, no family history) is heterozygous for the haplotype and provides no in-trans observation.
Population homozygote observations (gnomAD v2.1: 2; gnomAD v4.1: 21; gnomAD v3.1 non-cancer: 1) were examined for a possible allelic benign argument but are outside the generic ACMG/AMP 2015 BP2 definition, which requires a pathogenic partner variant in cis or trans; they are addressed by the benign-strength (BS2) and population-frequency groups rather than counted here.
No ClinGen CSPEC/VCEP or local AXIN2 gene framework exists for this case (case_summary.cspec.found=false; vcep_materials.json reports no CSPEC URL, no gene notes, and source=generic_acmg_fallback with framework_complete=false), so all four population criteria were adjudicated under generic ACMG/AMP 2015 with the published calibration values supplied for this case.
Because no governing VCEP specifies a non-cancer or exome-only population source, the all-comers GNOMAD_V2_1 and GNOMAD_V4_1 entries were the default sources; the GNOMAD_V2_1_NON_CANCER (exomes-only) and GNOMAD_V3_1_NON_CANCER (genomes-only) subsets were nevertheless evaluated in parallel and give identical conclusions for BA1, BS1 and PM2, as does the independent gnomAD-Canada v1.0 cohort.
None of BA1 (>= 5%), BS1 (>= 1%) or PM2 (<= 0.0001) is met: the highest credible population frequency (~0.55%) sits between the BS1 and BA1 thresholds and is roughly 30-45x the PM2 cutoff. The single value above 1% anywhere in the data (HGDP Mozabite 5.77%, 3/52 alleles, gnomAD v3.1 non-cancer genomes) is a small-sample artefact and cannot carry stand-alone or strong benign weight.
BS2 is not met: although gnomAD contains homozygotes for this variant (21 in v4.1, 2 in v2.1), gnomAD provides no individual-level health documentation, and the AXIN2-associated phenotype (oligodontia-colorectal cancer predisposition) is not fully penetrant at an early age, so the criterion's preconditions are not satisfied.
Net population-group contribution to the case: no benign or pathogenic point evidence from population data at the calibrated strengths - the frequency is too high for a rare fully penetrant dominant pathogenic role (and homozygotes are observed) but does not independently reach BA1/BS1.
No criteria match.
Met · 2
BS3SupportingMet at supporting strength: RT-PCR of the carrier's RNA showed c.1530G>A present in the same proportion as genomic DNA, indicating no splicing alteration.
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Reasoning
An RNA-based assay designed specifically to test the effect of AXIN2 c.1530G>A on splicing reports no damaging effect. In PMID:16941501, total RNA was extracted from the carrier's blood, reverse transcribed, amplified by RT-PCR with primers within exons 3 and 7 (i.e. spanning the exon containing the change), and the product was sequenced; c.1530G>A was present in the transcript at a similar proportion to genomic DNA, which the authors state indicated 'no splicing alteration'. The change is synonymous (p.Thr510=), so the protein sequence is unchanged and there is no protein-level consequence to detect; normal transcript processing on the carrier's own RNA plus an unaltered amino-acid sequence therefore constitutes functional evidence of no damaging effect, and independent splice prediction (SpliceAI max delta 0.001) is concordant. Calibration and strength: no AXIN2 VCEP or CSPEC specification exists, so generic ACMG/AMP 2015 applies, and PMID:25741868 expressly permits modifying criterion strength for evidence quality. The assay is reported only as a secondary observation within a mutation-screening case series — no wild-type/positive splicing controls, no replicates or quantitative transcript measurement, and no assay validation data are described — and it was performed in a single individual who carried c.1530G>A in cis with c.1235A>G (p.Asn412Ser), so the two changes were not independently resolved at the transcript level (although the transcript-versus-genomic ratio comparison addresses allele-specific transcript loss). BS3 is therefore applied at supporting strength rather than strong; the direction of the finding (no damaging effect) is well supported, but the assay quality and single-carrier design do not meet the bar for strong.
Rule
ACMG/AMP 2015 BS3: well-established functional studies show no damaging effect on protein function or splicing — met at supporting strength (single-carrier RNA RT-PCR showing no splicing alteration, no reported assay controls or validation).
Evidence considered
PMID:16941501 performed RT-PCR on the carrier's blood-derived RNA (primers within exons 3 and 7) and sequenced the product: c.1530G>A was present at a similar proportion to genomic DNA, which the authors interpreted as 'indicating no splicing alteration' — a direct functional test of the only mechanism by which this synonymous change could act.
The variant does not alter the amino-acid sequence (p.Thr510=), so no protein-level defect is expected; the combination of an unchanged protein and normally processed transcript on the carrier's own RNA is evidence of no damaging effect.
PMID:25741868 (ACMG/AMP 2015) allows the strength of a criterion to be modified according to the quality of the evidence; because the splicing assay is a secondary case-series observation with no stated controls, replicates or quantitative readout performed in a single carrier, BS3 was applied at supporting rather than strong strength.
SpliceAI max delta score 0.001 independently predicts no splice impact, concordant with the experimental result.
No AXIN2-specific VCEP or CSPEC specification exists for this gene, so generic ACMG/AMP 2015 BS3 criteria were applied.
Still missing
Assay provenance is thin: PMID:16941501 does not describe positive or negative splicing controls, replicates, quantitative transcript measurement, or assay validation, so the strength of BS3 was capped at supporting.
The RT-PCR was performed in one individual heterozygous for c.1530G>A in cis with c.1235A>G (p.Asn412Ser); no second carrier or independent cell system replicates the no-splice-effect result, and the variant was absent from the other 30 patients and 50 healthy controls screened.
No AXIN2-specific VCEP/CSPEC exists to supply a validated functional assay list or gene-specific BS3 strength calibration, so strength was assigned by generic ACMG/AMP quality-of-evidence judgement.
BP7SupportingMet, supporting: synonymous p.(Thr510=) with SpliceAI max delta 0.001, far below the 0.2 significant-impact cutoff.
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Reasoning
BP7 (Richards et al. 2015, PMID:25741868) applies to a synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and no creation of a new splice site. NM_004655.4:c.1530G>A is synonymous (NP_004646.3:p.(Thr510=)). SpliceAI returns DS_AG 0.001, DS_AL 0.001, DS_DG 0.00 and DS_DL 0.00, giving a maximum delta score of 0.001, and Pangolin gives splice-gain 0.002 / splice-loss -0.001; no cryptic acceptor or donor site is predicted. These values sit far below the SpliceAI recommended cutoff of 0.2 for significant splice impact (Jaganathan et al. 2019, PMID:30661751) and below the 0.1 no-impact level, so the predicted-splice-silence requirement is met. Independent experimental corroboration exists for this exact variant: transcript analysis by RT-PCR in a patient carrying c.1530G>A showed the variant present in the amplified cDNA at the same proportion as in genomic DNA, indicating no splicing alteration (Lejeune et al. 2006, PMID:16941501), and the same variant has since been reported as a synonymous/common finding in tooth-agenesis cohorts (PMID:29114927, PMID:30555066) without any demonstration of a splice effect. BP7 is therefore met at supporting strength. A quantitative nucleotide-conservation metric (e.g. phyloP/GERP) for this position was not available in the evidence reviewed; the position is not annotated as conserved, and the variant's appreciable population frequency in gnomAD v4.1 (AF 0.445%, 21 homozygotes) plus the concordant negative splice predictions and the negative RT-PCR result make a constrained, functionally relevant nucleotide at this position unlikely.
The variant is synonymous: NM_004655.4:c.1530G>A, NP_004646.3:p.(Thr510=), exon 6 of AXIN2.
SpliceAI scores for NM_004655.4:c.1530G>A are DS_AG 0.001, DS_AL 0.001, DS_DG 0.00, DS_DL 0.00; maximum delta score is 0.001, i.e. no predicted splice-acceptor or splice-donor gain or loss.
Pangolin scores for the same variant are splice-gain 0.002 and splice-loss -0.001, concordant with no predicted splice impact.
The SpliceAI recommended cutoff for significant splice impact is 0.2 (Jaganathan et al. 2019, PMID:30661751); the observed maximum delta of 0.001 is far below it and below the 0.1 no-impact level.
Lejeune et al. 2006 (PMID:16941501) performed RT-PCR on transcripts of a patient carrying this exact variant using primers within exons 3 and 7 and found the variant present at a similar proportion as in genomic DNA, indicating no splicing alteration; the variant was reported as an apparently silent change and the authors considered it likely to be a polymorphism.
PMID:29114927 reported this synonymous variant in 1/37 patients with non-syndromic tooth agenesis and noted that a splice-site effect should be considered, but presented no functional or transcript data showing any splice effect.
PMID:30555066 listed the codon-510 synonymous change (written as c.1531G>A, Thr510Thr, rs63533624 in that paper) among AXIN2 variants and classified all AXIN2 findings as common variants.
ClinVar (variation 136481) holds only Benign/Likely benign assertions for this variant (multiple clinical laboratories, no expert-panel submission), consistent with a benign synonymous change rather than a splice-altering one.
gnomAD v4.1 reports this variant at AF 0.445% (7188/1613744 alleles) with 21 homozygotes, and gnomAD v2.1 at AF 0.285% with 2 homozygotes, arguing against a highly constrained nucleotide position.
No AXIN2 gene-specific VCEP/CSpec specification or BP7 lookup table exists for this case (framework_mode = generic_acmg), so the generic ACMG/AMP 2015 BP7 definition with published SpliceAI thresholds was applied.
Still missing
No quantitative nucleotide-conservation metric (phyloP/GERP/phastCons) for the c.1530 position was present in the evidence reviewed; the no-splice-impact requirement of BP7 is nevertheless supported concordantly by SpliceAI, Pangolin and an independent patient RT-PCR study.
PS2Not met: no de novo occurrence of c.1530G>A is reported, and the carrier study states parental DNA samples were unavailable, so parentage was never tested.
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Reasoning
PS2 requires a de novo occurrence of the variant: present in the patient, absent in both parents by testing, with both parental samples shown by identity testing to be the biological parents (Richards et al. 2015, PMID:25741868). No source reports NM_004655.4:c.1530G>A (NP_004646.3:p.(Thr510=)) as a de novo event. The only study that reported this variant in a patient and screened relatives (Lejeune et al. 2006, PMID:16941501) states in its methods that parental DNA samples were unavailable, so neither parent was genotyped for the carrier; that carrier was an 18-year-old with 30 adenomatous polyps and no reported family history. The variant has since been observed only in isolated, unrelated probands: 1 of 37 Tunisian patients with non-syndromic tooth agenesis (PMID:29114927) and 1 eastern Slovak patient with non-syndromic hypodontia (PMID:30555066), neither with parental testing or a de novo claim. The ClinVar record (19 submissions, 2 stars, no expert panel) contains no reported de novo occurrence for this variant. With no parental genotype data, PS2 cannot be met; the required evidence (a negative parental test) does not exist for this variant.
Rule
ACMG/AMP 2015 PS2: confirmed de novo (both parental samples test negative; biological parentage confirmed by identity testing)
Evidence considered
ACMG/AMP 2015 (PMID:25741868) defines PS2 as a de novo variant with parental samples testing negative and biological parentage confirmed by identity testing.
PMID:16941501 reports c.1530G>A (p.Thr510Thr) in a single patient and states that parental DNA samples were not available; no de novo status was claimed by the authors, who instead called the two changes found in that patient 'likely to be polymorphisms'.
PMID:29114927 reports the same synonymous change (p.Thr510Thr, rs141014640) in 1 of 37 unrelated tooth-agenesis patients with no parental testing and no de novo claim.
PMID:30555066 reports the same codon-510 synonymous change in 1 patient, with no parental testing and no de novo claim.
The ClinVar record for variation 136481 (19 submissions, no expert panel) contains no submission asserting a de novo occurrence; this was used only to establish the absence of a de novo report, not as a classification argument.
Still missing
No trio/parental genotype data for c.1530G>A; the carrier proband's parents were not tested (PMID:16941501 states parental DNA samples were unavailable), so a de novo origin can be neither confirmed nor excluded.
PS3Not met: patient RNA RT-PCR across exons 3-7 showed c.1530G>A at the same proportion as genomic DNA, i.e. no splicing alteration.
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Reasoning
No well-established functional study demonstrates a damaging effect for AXIN2 c.1530G>A. The variant is synonymous (NP_004646.3:p.(Thr510=)), so the only plausible mechanism by which this nucleotide substitution could damage the gene product is altered splicing — and that mechanism was tested directly and found negative. PMID:16941501 performed RT-PCR on the carrier's blood-derived RNA with primers within exons 3 and 7 and sequenced the product; the variant was present at a similar proportion to that observed in genomic DNA, which the authors state indicated 'no splicing alteration', and they concluded the two exon-5 changes in that patient (c.1235A>G p.Asn412Ser and c.1530G>A p.Thr510Thr) were 'likely to be polymorphisms'. No minigene assay, quantitative transcript assay, or protein-function assay reporting a deleterious effect for this variant was found in any source consulted; PMID:29114927 and PMID:30555066 both report the codon-510 synonymous change in patient cohorts without performing any functional assay for it, and PMID:29114927 merely raises a possible splice-site effect as an untested hypothesis that the RT-PCR data in PMID:16941501 refute. Independent in-silico splice prediction is concordant: SpliceAI max delta score 0.001, i.e. no predicted splice impact. In-silico concordance does not substitute for functional data, but it removes any residual basis to expect an experimentally undetected damaging effect. PS3 is therefore not met at any strength.
Rule
ACMG/AMP 2015 PS3: well-established functional studies show a damaging effect on gene or gene product — not satisfied (no assay reports a damaging effect; the only RNA assay is negative).
Evidence considered
PMID:16941501 experimentally tested the splicing effect of this exact change: RNA was extracted from the carrier's blood, reverse transcribed, amplified with primers within exons 3 and 7, and the product sequenced; both exon-5 variants (c.1235A>G and c.1530G>A) were present at a similar proportion to that seen in genomic DNA, 'indicating no splicing alteration' (Results, AXIN2 Gene Analysis).
Because c.1530G>A is synonymous (p.Thr510=), altered splicing is the only plausible mechanism by which this nucleotide change could exert a damaging effect; that mechanism was tested and negative, and the authors concluded the two variants were 'likely to be polymorphisms'.
PMID:26467025 (a CLIA laboratory's rules-based scoring system, 11,894 variants/338 genes) reports that only ~1% of synonymous changes scored in the pathogenic range while 96% scored in the benign range, and states that published transcript-splicing assays were generally counted as functional evidence of pathogenicity only when the aberrant splicing caused mRNA truncation in a haploinsufficient disease model; no truncating aberrant transcript is reported here.
PMID:25741868 (ACMG/AMP 2015) notes that synonymous/splice-region effects may require functional RNA or protein analysis to confirm; the available RNA analysis for this variant is negative.
SpliceAI max delta score 0.001 (DS_AG 0.001, DS_AL 0.001, DS_DG 0.0, DS_DL 0.0) predicts no splice impact, consistent with the negative RT-PCR result.
No AXIN2-specific VCEP or CSPEC specification exists for this gene, so generic ACMG/AMP 2015 PS3 criteria were applied.
Still missing
No functional assay capable of demonstrating a damaging effect exists for this variant — no minigene splicing assay with wild-type and positive controls, no quantitative transcript assay, and no protein-level assay were reported in any source consulted.
No AXIN2-specific VCEP/CSPEC specification exists, so no gene-specific functional-assay calibration or approved assay list is available to define what would constitute 'well-established' functional evidence for PS3 for this gene.
PS4Not met: three case series each report this variant in one affected individual with no odds ratio or significant case-control enrichment, while gnomAD v4.1 shows AF 0.445% with 21 homozygotes.
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Reasoning
PS4 (Richards et al. 2015, PMID:25741868) requires a statistically significant increase in variant frequency in affected individuals compared with controls. No ClinGen CSPEC/VCEP and no local gene-specific framework exists for AXIN2 (CSPEC search returned nothing; the classification framework resolved to generic_acmg_fallback with framework_complete=false), so the generic ACMG/AMP 2015 definition applies. No numeric PS4 threshold was available: neither the governing specification (none exists for AXIN2) nor the supplied published-threshold block contains a PS4 odds-ratio or relative-risk cutoff, so no numeric inequality comparison was performed for this criterion and enrichment was assessed qualitatively from the retrieved cohort data. Three retrieved papers carry this exact variant as single observations in affected cohorts, none as a statistically enriched signal. (1) PMID:16941501 screened AXIN2 in 31 patients with multiple adenomatous polyps or colorectal cancer and reported c.1530G>A (p.Thr510Thr) in one 18-year-old patient with 30 adenomatous polyps; the variant was absent in the 30 other patients and in 50 healthy controls, no association statistic was computed, and the authors concluded the two AXIN2 changes they found were 'likely to be polymorphisms'. (2) PMID:29114927 found the variant in 2.7% of patients (1 of 37) with non-syndromic tooth agenesis, attributed no pathogenic role to it, and did not include it in the chi-square case-control association analysis. (3) PMID:30555066 listed the same codon-510 synonymous change (reported there as c.1531G>A, rs63533624) in 1 of 60 eastern Slovak non-syndromic hypodontia patients, described all AXIN2 findings as common variants and excluded them from the association analysis. No odds ratio, relative risk, confidence interval or p-value for this variant was reported in any retrieved source. Population data argue against case enrichment at the sizes of these cohorts: gnomAD v4.1 AF 0.445% (7188/1613744 alleles, 21 homozygotes; non-Finnish European AF 0.553%) and gnomAD v2.1 AF 0.285% (806/282518 alleles, 2 homozygotes; non-Finnish European AF 0.489%). The exact-variant ClinVar record (VCV000136481, 19 submissions, no expert panel) is Benign/Likely benign. PS4 is therefore not met.
Rule
generic_acmg_PS4_case_control_enrichment (Richards et al. 2015, PMID:25741868); no AXIN2 VCEP/CSPEC rule and no published PS4 odds-ratio cutoff available, so no numeric comparison applied
Evidence considered
Generic ACMG/AMP 2015 PS4 definition (case-control/case-enrichment) applied because no ClinGen CSPEC/VCEP exists for AXIN2 and no local gene framework was supplied (vcep_materials.json: 'no cspec url available'; final_classification_framework: source=generic_acmg_fallback, precedence_rank=3, framework_complete=false).
The supplied published-threshold block contains no PS4 odds-ratio or relative-risk cutoff, and no governing VCEP specification provides one for this gene, so no numeric PS4 threshold was available and no inequality comparison direction was applied; enrichment was judged qualitatively.
PMID:16941501: germline screening of AXIN2 (NM_004655.2, exons 1-10) in 31 unrelated patients with multiple adenomatous polyps or colorectal cancer without APC mutation or MMR defect; c.1530G>A found in one 18-year-old patient with 30 adenomatous polyps, absent in the other 30 patients and in 50 healthy controls; authors state the changes were 'likely to be polymorphisms'.
PMID:29114927: Tunisian case-series of 37 patients with non-syndromic tooth agenesis plus 88 dentate controls; c.1530G>A (p.Thr510Thr, rs141014640) at 2.7% (1/37 patients); reported allele frequencies 0.001 (A) in African and 0 (A) in European reference populations; the variant was not among the variants carried into the chi-square case-control analysis and no pathogenic role was assigned to it.
PMID:30555066: Sanger sequencing of WNT10A, PAX9 and AXIN2 in 60 unrelated eastern Slovak patients with non-syndromic hypodontia plus 48 healthy controls; the same codon-510 synonymous change (c.1531G>A, Thr510Thr, rs63533624) present in 1 patient; authors classified the AXIN2 findings as common variants and excluded them from further association analysis.
Population-frequency context against enrichment at the reported cohort sizes: gnomAD v4.1 AF 0.445% (7188/1613744 alleles, 21 homozygotes; non-Finnish European AF 0.553%, 6527/1179970 alleles, 17 homozygotes) and gnomAD v2.1 AF 0.285% (806/282518 alleles, 2 homozygotes; non-Finnish European AF 0.489%, 631/128970 alleles).
Exact-variant ClinVar record VCV000136481 (ClinVarID 136481): 19 submissions, aggregate Benign/Likely benign, review status 'criteria provided, multiple submitters, no conflicts' (2 stars), expert_panel_submissions = 0.
Still missing
No case-control or cohort study reporting an odds ratio, relative risk or significance test for AXIN2 c.1530G>A was located; because no PS4 numeric threshold exists in the governing framework or the supplied published-threshold block, PS4 cannot be raised even if a small cohort enrichment were claimed.
PM2Not met: allele frequency 0.285%-0.445% in gnomAD is roughly 30-45x the 0.0001 supporting PM2 threshold.
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Reasoning
PM2 is the ACMG/AMP 2015 criterion for a variant that is absent from, or at extremely low frequency in, a large general-population or control cohort (Richards et al. 2015, PMID:25741868); in its current SVI-downgraded supporting form the applicable cutoff supplied for this case is an allele frequency <= 0.0001 (0.01%). This variant is far above that everywhere it is measured: gnomAD v4.1 all-comers total AF 0.00445424 (7,188/1,613,744 alleles), i.e. about 45x the PM2 threshold, with 21 homozygotes and a grpmax FAF of 0.00541925; gnomAD v2.1 all-comers total AF 0.00285292 (806/282,518), about 29x the threshold. The maximum ancestry frequency is 0.00553150 in European (non-Finnish) (gnomAD v4.1). Checking non-cancer sources does not rescue rarity: gnomAD v2.1 non-cancer exomes (the exome-only source an older specification would prefer) give 0.00293581 (695/236,732) and gnomAD v3.1 non-cancer genomes give 0.00291403 (430/147,562), with gnomAD-Canada v1.0 at 0.00337397 (62/18,376). The variant is also present on multiple haplotypes/ancestries (African/African American 0.00243, Admixed American 0.00243) rather than being confined to one ancestry, and it is seen in three independent population cohorts, which argues against a cohort-specific ascertainment artifact. Literature frequency statements are consistent with this: PMID:29114927 reports ExAC/Ensembl-based frequencies of 0.001 (African) and 0 (European), 0.002 overall - still 10-20x above the PM2 cutoff - and PMID:16941501 found the variant absent from 50 healthy controls and 30 other polyposis patients, a cohort far too small to establish population rarity. Because the allele frequency exceeds the 0.0001 threshold by roughly 30-45 fold, PM2 cannot be applied even at supporting strength, and no constraint exists that would lower the threshold for this gene (no AXIN2 CSPEC/VCEP; generic ACMG fallback). PM2 is not met.
Rule
PM2 (supporting, SVI-downgraded): allele frequency <= 0.0001, ClinGen SVI 2020 (PMID:25741868); generic ACMG fallback, no AXIN2 CSPEC/VCEP available
Evidence considered
gnomAD v4.1 all-comers: total AF 0.00445424 (7,188/1,613,744; 21 homozygotes), exome 0.00461475, genome 0.00290962, grpmax FAF 0.00541925 - roughly 45x the 0.0001 PM2 cutoff.
gnomAD v2.1 all-comers: total AF 0.00285292 (806/282,518; 2 homozygotes), exome 0.00293347, genome 0.00220588, grpmax FAF 0.0047191 - roughly 29x the 0.0001 cutoff.
gnomAD v2.1 non-cancer exomes-only subset (exome-only source an older specification would use): AF 0.00293581 (695/236,732) - not rare under any non-cancer calibration.
gnomAD v3.1 non-cancer genomes-only subset: AF 0.00291403 (430/147,562) - confirms the frequency is not an artefact of including cancer cohorts.
gnomAD-Canada v1.0 (HostSeq genomes): AF 0.00337397 (62/18,376) - third independent cohort at ~0.3%.
Ancestry distribution shows the variant is not confined to one population (e.g. African/African American 0.00100 in v2.1, Admixed American 0.00243, European non-Finnish 0.00489), which argues against a single-cohort ascertainment artefact.
ACMG/AMP 2015 PM2 definition verbatim (PMID:25741868): 'If a variant is absent from (or below the expected carrier frequency if recessive) a large general population or a control cohort (>1000 individuals) and the population is race-matched to the patient harboring the identified variant, then this observation can be considered a moderate piece of evidence for pathogenicity (PM2).'
PMID:29114927 (Haddaji Mastouri et al. 2018) reports this exact variant, c.1530G>A p.Thr510Thr rs141014640, in a Tunisian non-syndromic tooth agenesis cohort and states ExAC/Ensembl-based allele frequencies of 0.001 (A) in the African population and 0 (A) in the European population ('0.002 overall'), which are also above the 0.0001 PM2 cutoff.
PMID:16941501 (Lejeune et al. 2006) reports this exact variant as an 'apparently silent' exon 5 change in a polyposis patient and notes it was absent from 30 other screened patients and 50 healthy controls - a control cohort far below the >1000 individuals the ACMG guidance expects, so it cannot establish rarity.
PMID:30555066 (Grejtakova et al. 2018) lists the same codon-510 synonymous change (reported there as c.1531G>A, Thr510Thr, DB_SNP build 129 rs63533624) in 1 of 60 hypodontia patients and classifies the AXIN2 findings as common variants; no population allele frequency is supplied.
Generic SVI PM2 downgrade to supporting with cutoff <= 0.0001 applied verbatim; no AXIN2 CSPEC/VCEP or local framework exists to modify it.
Still missing
No AXIN2-specific PM2 threshold or carrier-frequency constraint exists (cspec.found=false, no VCEP, framework_complete=false), so the generic <= 0.0001 supporting cutoff was applied; even a relaxed reading would not be satisfied at a frequency of ~0.3%.
The literature control cohort (50 healthy controls, PMID:16941501) is far smaller than the >1000-individual cohort the ACMG frequency guidance contemplates, so literature absence cannot substitute for gnomAD frequency data in either direction.
PM3Not met: no affected proband carries c.1530G>A in trans with a pathogenic AXIN2 variant; the only phase-resolved observation is in cis (PMID:16941501).
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Reasoning
PM3 (Richards et al. 2015, PMID:25741868) requires the variant to be detected in trans with a pathogenic variant, i.e. a phase-resolved second pathogenic allele on the opposite chromosome, with the classic setting being an affected proband in a recessive disorder. AXIN2-associated disease is inherited in an autosomal dominant pattern for every phenotype recorded for this variant (ClinVar conditions 'Oligodontia-cancer predisposition syndrome' and 'Hereditary cancer-predisposing syndrome'; AXIN2 germline literature retrieved into the gene-context evidence, e.g. PMID:41361419, documents autosomal dominant inheritance of AXIN2-associated tooth agenesis and polyposis), and no ClinGen CSPEC/VCEP or local AXIN2 framework exists (cspec.found=false; vcep_materials.json source=generic_acmg_fallback, framework_complete=false), so the generic ACMG/AMP 2015 definition governs without gene-specific reweighting. No source in this case reports c.1530G>A in trans with a pathogenic or likely pathogenic AXIN2 variant. The single phase-resolved observation runs the other way: PMID:16941501 reports this variant together with a missense change in one 18-year-old patient with 30 adenomatous polyps and no family history (Results text names patient Li-10; Table 2 lists the same genotype under Li-9), with the genotype written c.[1235A>G (+) 1530G>A] / p.[Asn412Ser (+) Thr510Thr] - the '(+)' notation placing both changes in cis on one allele. That cis partner, p.Asn412Ser, is not an established pathogenic variant: PolyPhen predicted it benign, RT-PCR from exons 3-7 showed both variants at the same proportion as in genomic DNA (no splicing alteration), and the authors concluded the two changes 'are likely to be polymorphisms'. The other patient-based reports of this variant (PMID:29114927, 1 of 37 Tunisian tooth-agenesis patients; PMID:30555066, one eastern Slovak hypodontia patient) are heterozygous observations with no second AXIN2 variant, phase, segregation or biallelic data. PM3's required in-trans configuration is therefore absent, and the population homozygote observations (gnomAD v2.1: 2 homozygotes; v4.1: 21) describe the variant in double dose rather than in trans with a pathogenic allele. PM3 is not met.
Rule
For recessive disorders, detected in trans with a pathogenic variant (Richards et al. 2015, PMID:25741868).
Evidence considered
Generic ACMG/AMP 2015 PM3 definition applied (PMID:25741868): the variant must be detected in trans with a pathogenic variant; no AXIN2 CSPEC/VCEP or local AXIN2 framework exists (cspec.found=false; vcep_materials.json source=generic_acmg_fallback, framework_complete=false), so no gene-specific PM3 reweighting is available for this autosomal dominant gene.
Phase evidence for this exact variant, PMID:16941501 Table 2 (AXIN2 section): patient Li-9 is listed as c.[1235A>G (+) 1530G>A] / p.[Asn412Ser (+) Thr510Thr], where the '(+)' notation denotes two changes in cis on the same allele; the Results text attributes the same two variants to the 18-year-old patient Li-10 with 30 adenomatous polyps and no family history.
The cis partner variant p.Asn412Ser is not a pathogenic variant: PolyPhen predicted it benign on the basis of limited Asn conservation, RT-PCR with primers in exons 3 and 7 showed both variants present at a similar proportion as in genomic DNA (indicating no splicing alteration), and the authors stated the two variations 'are likely to be polymorphisms' (PMID:16941501).
Other patient-based sources reporting this variant provide no in-trans or biallelic data: PMID:29114927 (1 of 37 Tunisian non-syndromic tooth agenesis patients, p.Thr510Thr rs141014640, not among the five variants highlighted as probably disease-causing) and PMID:30555066 (one eastern Slovak hypodontia patient, listed as c.1531G>A/p.Thr510Thr rs63533624, with all AXIN2 findings classified as common variants).
Inheritance mode: the AXIN2-associated phenotypes recorded for this variant (ClinVar conditions 'Oligodontia-cancer predisposition syndrome' and 'Hereditary cancer-predisposing syndrome') are autosomal dominant, and the AXIN2 germline literature retrieved into the gene-context evidence (pvs1_gene_context; e.g. PMID:41361419, in which the AXIN2 c.1060-3T>C variant was inherited from the father in an autosomal dominant pattern) gives no recessive AXIN2 disease model that would make an in-trans pathogenic allele the expected configuration.
Population genotype data were checked for a biallelic configuration: gnomAD v2.1 reports 806/282,518 alleles (AF 0.28529%) with 2 homozygotes and gnomAD v4.1 reports 7,188/1,613,744 alleles (AF 0.44542%) with 21 homozygotes; these homozygote observations show the variant in double dose in population samples, not in trans with a pathogenic variant, and therefore cannot support PM3.
Still missing
No phase-resolved genotype placing c.1530G>A in trans with a pathogenic or likely pathogenic AXIN2 variant exists in any case source, so the criterion's trigger could not be evaluated positively.
No AXIN2 CSPEC/VCEP or local gene-specific framework exists to extend or reweight PM3 for an autosomal dominant gene context; only the generic ACMG/AMP 2015 definition was available.
PMID:16941501 is internally inconsistent about the patient identifier carrying the cis haplotype (Results text: Li-10; Table 2: Li-9); both placements describe the same two-variant cis genotype, so the phase call itself is unaffected.
PM6Not met: no report describes c.1530G>A as arising de novo, and without parental DNA even an assumed de novo event cannot be claimed.
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Reasoning
PM6 requires an assumed de novo occurrence - a de novo event reported when biological parentage has not been confirmed by identity testing (Richards et al. 2015, PMID:25741868). It therefore still requires an actual report of the variant having arisen de novo. No source describes NM_004655.4:c.1530G>A (p.(Thr510=)) as a de novo event in any patient. PMID:16941501 is the only study that both detected the variant in a patient and examined that patient's family, and it records that parental DNA samples were unavailable; the variant was inherited-status-unknown and was interpreted by those authors as likely a polymorphism rather than as a new mutation. PMID:29114927 and PMID:30555066 each report the variant in a single unrelated patient and provide no transmission analysis. PS2 and PM6 therefore fail for the same reason: the missing parental testing that PM6 relaxes is not the obstacle - there is simply no report of a de novo occurrence, assumed or confirmed, for this variant.
Rule
ACMG/AMP 2015 PM6: assumed de novo variant (parentage assumed but not confirmed)
Evidence considered
ACMG/AMP 2015 (PMID:25741868) states that PM6 applies when parentage is assumed but not confirmed, i.e. it still requires an observed de novo variant.
PMID:16941501 reports the variant in one polyposis patient and explicitly notes the absence of parental DNA samples, so no de novo event, confirmed or assumed, was established; the authors interpreted the change as likely polymorphic.
PMID:29114927 and PMID:30555066 each report the variant in a single unrelated patient with no family transmission analysis.
The ClinVar record for this variant (19 submissions, no expert panel) carries no de novo assertion.
Still missing
No report of a de novo occurrence, even with unconfirmed parentage; parental genotypes are absent for every carrier reported in the literature, and the case supplies no proband or parental data.
PP1Not met: zero informative meioses - no genotyped pedigree for c.1530G>A is reported, so co-segregation with disease is unestablished.
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Reasoning
PP1 requires co-segregation of the variant with disease in multiple affected family members of a family in which the gene is known to cause disease (Richards et al. 2015, PMID:25741868). No segregation analysis of NM_004655.4:c.1530G>A (p.(Thr510=)) exists in any available source; zero informative meioses carrying this variant have been reported. PMID:16941501 screened 31 unrelated polyposis probands and found the variant in a single patient with no reported family history and no genotyping of relatives - no meiosis count, LOD score or pedigree is provided for this change. PMID:29114927 studied 9 familial cases among 37 tooth-agenesis patients but reports this change in only 1 patient, provides no co-segregation of the variant, and excluded it from its case-control analysis. PMID:30555066 detected it in one patient with no family testing. PMID:26467025 documents that family segregation evidence is scored by informative meioses/LOD, but supplies no variant-level data for this change. In the absence of any genotyped pedigree, PP1 is not met; the case itself provides no family or meiosis data because no proband pedigree was supplied.
Rule
ACMG/AMP 2015 PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
Evidence considered
ACMG/AMP 2015 (PMID:25741868) defines PP1 as co-segregation with disease in multiple affected family members.
PMID:16941501 is the only study reporting this variant together with study of relatives' disease (31 unrelated polyposis probands and their families by pedigree/table), yet it reports the variant in one patient with no family history and genotypes no relatives for it; no shared haplotype, meiosis or LOD data are given for c.1530G>A.
PMID:29114927 includes 9 familial non-syndromic tooth-agenesis patients but reports c.1530G>A in only 1 of 37 patients and performs no segregation or co-segregation test on it; the variant was not among the variants highlighted as probably disease-causing.
PMID:30555066 reports the same codon-510 synonymous change in a single patient with no family testing.
PMID:26467025 was consulted for how segregation evidence is quantified in a rules-based scoring system (LOD estimated from meiotic events, family segregation data moving scores toward pathogenicity); it contains no data on AXIN2 or this variant and therefore contributed no criterion-level evidence.
Still missing
No pedigree with genotype data for c.1530G>A in affected relatives; no meiosis count or LOD score is reported by any source. Co-segregation could be assessed only by genotyping affected relatives of the reported carriers, which no source performed.
PP5Not met: the exact-variant ClinVar record (ClinVarID 136481, 19 laboratory submissions) has zero expert-panel submissions, so no Pathogenic expert-panel source exists.
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Reasoning
PP5 is applied here only for an exact-variant ClinVar classification issued by an expert panel (ClinGen VCEP/Expert Panel) that asserts Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels and non-expert assertions must never trigger it. The exact-variant record NM_004655.4(AXIN2):c.1530G>A (p.Thr510=), VCV000136481 / ClinVarID 136481, contains 19 submissions from clinical laboratories, zero expert-panel submissions (source_data.expert_panels is empty; the submission audit records expert_panel_submissions = 0 and is_expert_panel = false for every individual submission), and a 2-star review status ('criteria provided, multiple submitters, no conflicts'); the aggregate label is Benign/Likely benign. No expert-panel Pathogenic or Likely pathogenic classification of this exact variant exists in the retrieved sources, and no ClinGen CSPEC/VCEP specification exists for AXIN2 (CSPEC search returned nothing; vcep_materials reports 'no cspec url available'). PMID:25394175, the ACMG/NSGC cancer-predisposition referral practice guideline flagged during triage as a PP5 lead, neither mentions AXIN2 nor this variant, so it cannot supply a reputable-source pathogenic assertion. PP5 is therefore not met.
Rule
PP5_expert_panel_exact_variant_pathogenic (ClinGen VCEP/Expert Panel only; ordinary laboratory submissions, aggregate ClinVar labels and non-expert assertions excluded); generic ACMG/AMP 2015 fallback since no AXIN2 specification exists
Evidence considered
Exact-variant ClinVar record NM_004655.4(AXIN2):c.1530G>A (p.Thr510=), VCV000136481 / ClinVarID 136481: 19 submissions from 19 submitters, review status 'criteria provided, multiple submitters, no conflicts' (2 stars, date last updated 2026-06-20), aggregate classification Benign/Likely benign.
Expert-panel check on the exact record: source_data.expert_panels is an empty object, and the per-submission audit reports expert_panel_submissions = 0 and is_expert_panel = false for all 19 submissions, so no expert-panel assertion of any direction exists for this variant.
Submission breakdown in the exact record: Benign (8 clinical laboratories), Likely benign (8 clinical laboratories), benign (1 clinical laboratory) - all ordinary laboratory assertions, which the criteria instruction for this group excludes from PP5 regardless of direction.
No ClinGen CSPEC/VCEP exists for AXIN2: the CSPEC lookup found nothing (found=false, no version/title), and vcep_materials records 'no cspec url available' with no gene VCEP files; the classification framework is the generic ACMG/AMP 2015 fallback.
PMID:25394175 (ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment), flagged in triage as a PP5 candidate source, contains no mention of AXIN2 or of c.1530G>A; it lists referral criteria by tumour type/syndrome and cannot provide a reputable-source pathogenic assertion for this variant.
ACMG/AMP 2015 PP5 definition used as the generic fallback (Richards et al. 2015, PMID:25741868): a reputable source reporting the variant as pathogenic, with the group instruction restricting acceptance to an exact-variant expert-panel Pathogenic/Likely pathogenic classification.
Still missing
No ClinGen VCEP/Expert Panel has issued a classification for this variant, and no AXIN2-specific expert specification exists to consult; PP5's premise is affirmatively absent in the retrieved data rather than merely unevaluated.
BA1Not met: highest population frequency is 0.553% in gnomAD v4.1 European (non-Finnish), far below the 5% BA1 stand-alone threshold.
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Reasoning
BA1 (Richards et al. 2015, PMID:25741868) is stand-alone benign evidence when the allele frequency exceeds 5% ('if over 5% then it is considered as stand-alone support (BA1)'). No gnomAD dataset or ancestry group approaches that. gnomAD v4.1 all-comers: total AF 0.00445424 (7,188/1,613,744 alleles; 21 homozygotes), grpmax FAF 0.00541925, and the highest ancestry frequency 0.00553150 in European (non-Finnish) (6,527/1,179,970; 17 homozygotes). gnomAD v2.1 all-comers: total AF 0.00285292 (806/282,518; 2 homozygotes), European (non-Finnish) 0.00489261 (631/128,970; 2 homozygotes), grpmax FAF 0.0047191. The exome-only non-cancer subsets are concordant and do not raise the figure (v2.1 non-cancer exomes 0.00293581, 695/236,732, European non-Finnish 0.00503467; v3.1 non-cancer genomes 0.00291403, 430/147,562, homozygotes 1; genome-only grpmax FAF 0.00473281), and the independent gnomAD-Canada v1.0 (HostSeq) cohort gives 0.00337397 (62/18,376; 0 homozygotes). The only frequency anywhere above 1% is the HGDP Mozabite subpopulation in gnomAD v3.1 non-cancer genomes, 0.0576923 (3/52 alleles), which is a small-sample threshold artifact rather than a population frequency: it rests on three alt alleles in a 52-allele sample (approximate 95% CI 2.0%-15.7%), it is not the grpmax population of that dataset (grpmax FAF 0.00473281), and it is not reproduced in any population-scale cohort (all other cohorts and ancestries 0%-0.55%). Because every population-scale frequency measured in this variant is 0.55% or below, the 5% stand-alone threshold is not reached. BA1 is not met.
Rule
BA1 (stand-alone benign): allele frequency >= 0.05, ACMG/AMP 2015 (PMID:25741868); generic ACMG fallback, no AXIN2 CSPEC/VCEP available
Evidence considered
gnomAD v4.1 (all-comers, GRCh38 chr17-65537506-C-T): total AF 0.00445424 (7,188/1,613,744), 21 homozygotes; exome AF 0.00461475 (6,746/1,461,834), 20 homozygotes; genome AF 0.00290962 (442/151,910), 1 homozygote; grpmax FAF 0.00541925.
gnomAD v4.1 highest ancestry group: European (non-Finnish) AF 0.00553150 (6,527/1,179,970), 17 homozygotes.
gnomAD v2.1 (all-comers, GRCh37 17-63533624-C-T): total AF 0.00285292 (806/282,518), 2 homozygotes; exome AF 0.00293347 (737/251,238), 2 homozygotes; genome AF 0.00220588 (69/31,280), 0 homozygotes; grpmax FAF 0.0047191; European (non-Finnish) AF 0.00489261 (631/128,970), 2 homozygotes.
gnomAD v2.1 non-cancer exome-only subset (checked because a non-cancer/exome-only source is the preferred input for older VCEP specifications; no such specification applies here): total exome AF 0.00293581 (695/236,732), 2 homozygotes; exome grpmax FAF 0.00487629; European (non-Finnish) AF 0.00503467 (594/117,982).
gnomAD v3.1 non-cancer genomes-only subset (v3 has no exome cohort): AF 0.00291403 (430/147,562), 1 homozygote; grpmax FAF 0.00473281.
gnomAD v3.1 non-cancer outlier: highest observed single subpopulation is HGDP:Mozabite AF 0.0576923 = 3/52 alleles, 0 homozygotes - a small-sample artifact (three alt alleles in a 52-allele sample), not the grpmax population and not reproducible in any population-scale cohort.
gnomAD-Canada v1.0 (HostSeq genomes, GRCh38): AF 0.00337397 (62/18,376), 0 homozygotes - independent confirmation that the variant sits at ~0.3% and no cohort reports a frequency near 5%.
ACMG/AMP 2015 frequency guidance verbatim (PMID:25741868): 'In general, an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1) or if over 5% then it is considered as stand-alone support (BA1).'
No CSPEC or local gene framework exists for AXIN2 and no VCEP population-source instruction was found (case_summary.cspec.found=false; vcep_materials.json framework found=false, source=generic_acmg_fallback), so the all-comers GNOMAD_V2_1 / GNOMAD_V4_1 entries are the default sources; the non-cancer subsets were evaluated in parallel and give the same conclusion.
Still missing
No AXIN2-specific ClinGen CSPEC/VCEP specification exists (framework_mode=generic_acmg, framework_complete=false), so no gene-specific stand-alone benign frequency threshold overrides the generic 5% BA1 value; the all-comers gnomAD totals remain the applicable source.
No frequency data from a population isolate or founder cohort with a large sample was available; the one outlying ancestry value (HGDP Mozabite 5.77%) is based on only 52 alleles and cannot be used as a stand-alone frequency.
BS1Not met: maximum population frequency is 0.553% (gnomAD v4.1 non-Finnish European) versus the 1% BS1 threshold.
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Reasoning
BS1 (Richards et al. 2015, PMID:25741868) applies when the allele frequency is greater than expected for the disorder at strong strength; the generic default supplied for this case is >= 0.01 (1%), which derives from gene-specific maximum-credible-frequency methods (Whiffin et al. 2017, PMID:28518168). No gnomAD dataset reaches 1%. gnomAD v4.1 all-comers total AF 0.00445424 (7,188/1,613,744; 21 homozygotes) with grpmax FAF 0.00541925; the maximum ancestry value is 0.00553150 in European (non-Finnish). gnomAD v2.1 all-comers total AF 0.00285292 (806/282,518) with grpmax FAF 0.0047191 and European (non-Finnish) 0.00489261. The exome-only non-cancer v2.1 subset that an older exome-calibrated specification would prefer is slightly higher but still well under the threshold (total 0.00293581, European non-Finnish 0.00503467, exome grpmax FAF 0.00487629), and the v3.1 non-cancer genomes subset is 0.00291403 (grpmax FAF 0.00473281); using non-cancer rather than all-comers sources therefore does not change the verdict. gnomAD-Canada v1.0 gives 0.00337397. The single value above 1% in the entire dataset is HGDP Mozabite (gnomAD v3.1 non-cancer genomes), 0.0576923 = 3/52 alleles - a sample-size artifact that cannot carry strong benign evidence, is not the grpmax population for its own dataset, and is unsupported by v2.1, v4.1 or gnomAD-Canada. A gene-specific BS1 threshold derived by the Whiffin approach could in principle fall below the generic 1% default for a dominant, variably penetrant cancer-predisposition gene, but the required AXIN2 inputs (disease prevalence, penetrance, allelic heterogeneity, locus heterogeneity) are not available in this case and no AXIN2 CSPEC/VCEP specification exists, so the generic 1% default governs. BS1 is not met.
Rule
BS1 (strong benign): allele frequency >= 0.01, generic SVI default derived from Whiffin et al. 2017 (PMID:28518168); generic ACMG fallback, no AXIN2 CSPEC/VCEP available
Evidence considered
gnomAD v4.1 all-comers total AF 0.00445424 (7,188/1,613,744 alleles; 21 homozygotes), grpmax FAF 0.00541925; highest ancestry European (non-Finnish) 0.00553150 (6,527/1,179,970; 17 homozygotes); no ancestry group reaches 1%.
gnomAD v2.1 all-comers total AF 0.00285292 (806/282,518; 2 homozygotes), grpmax FAF 0.0047191; European (non-Finnish) 0.00489261 (631/128,970).
gnomAD v2.1 non-cancer exomes-only subset (the exome-only source an older specification calibrated against gnomAD v2.1 exomes would use): AF 0.00293581 (695/236,732), European (non-Finnish) 0.00503467, exome grpmax FAF 0.00487629 - still below 1%.
gnomAD v3.1 non-cancer genomes-only subset: AF 0.00291403 (430/147,562), grpmax FAF 0.00473281 - still below 1%.
Threshold artifact flagged: the only frequency above 1% anywhere is HGDP:Mozabite in gnomAD v3.1 non-cancer genomes, 0.0576923 (3/52 alleles); three alt alleles in a 52-allele sample, not the dataset grpmax population, and not reproduced by v2.1, v4.1 or gnomAD-Canada.
ACMG/AMP 2015 frequency guidance verbatim (PMID:25741868): 'In general, an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1) or if over 5% then it is considered as stand-alone support (BA1).'
Generic SVI BS1 default of >= 0.01 was applied verbatim; the panel's own guidance notes per-gene derivation (Whiffin et al. 2017, PMID:28518168) is preferred, but the necessary AXIN2 prevalence/penetrance parameters were not available and no AXIN2 CSPEC/VCEP exists to supply them, so no gene-specific override was applied.
Still missing
No gene-specific (Whiffin-style) BS1 frequency threshold could be derived for AXIN2: disease prevalence, penetrance and allelic/locus heterogeneity inputs for oligodontia-colorectal cancer predisposition were not available in the case materials, and no AXIN2 VCEP/CSPEC specification exists. The generic 1% default was therefore used.
No large isolate/founder cohort frequency was available to test whether the outlying HGDP Mozabite observation (3/52 alleles) reflects a genuine local enrichment; the sample is too small either way to meet BS1.
BS2Not met: gnomAD homozygotes exist (21 in v4.1) but lack the documented healthy-adult status and early-age full penetrance that BS2 requires.
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Reasoning
BS2 (Richards et al. 2015, PMID:25741868) requires that 'the disease under investigation is fully penetrant at an early age and the variant is observed in a well-documented healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) condition'. Homozygotes are not absent from population data: gnomAD v4.1 reports 21 homozygotes (17 of them European non-Finnish, 20 in the exome subset, 1 in the genome subset) and gnomAD v2.1 reports 2 homozygotes (both European non-Finnish, both exome); the v2.1 non-cancer exome subset also reports 2 homozygotes and the v3.1 non-cancer genome subset 1. However, gnomAD provides no individual-level health or phenotype documentation, so none of these individuals is a 'well-documented healthy adult' in the sense BS2 requires; the database's own exclusions address severe paediatric disease, not adult-onset phenotypes. The second precondition also fails: the AXIN2-associated phenotype for which this variant was tested (ClinVar conditions for this record include 'Oligodontia-cancer predisposition syndrome' and 'Hereditary cancer-predisposing syndrome') is a variably penetrant, largely adult-onset adenomatous polyposis / colorectal cancer predisposition, not a disorder that is fully penetrant at an early age. An adult population participant carrying this synonymous change is therefore entirely compatible with being an affected carrier, and the homozygote observations cannot be converted into strong benign evidence. BS2 is not met.
Rule
BS2 (strong benign): variant observed in a well-documented healthy adult for a disorder fully penetrant at an early age, ACMG/AMP 2015 (PMID:25741868)
Evidence considered
gnomAD v4.1 homozygote counts: 21 total (20 exome, 1 genome), including 17 in European (non-Finnish); gnomAD v2.1: 2 homozygotes (both European non-Finnish, both exome).
gnomAD does not publish individual-level health status or phenotype, so the observed homozygotes do not satisfy BS2's requirement of a well-documented healthy adult; gnomAD's curation removes severe paediatric disease, not adult-onset phenotypes.
ACMG/AMP 2015 BS2 definition verbatim (PMID:25741868): 'Furthermore, if the disease under investigation is fully penetrant at an early age and the variant is observed in a well-documented healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) condition then this is considered strong evidence for a benign interpretation (BS2).'
Disease-context check: the conditions attached to this variant in ClinVar include 'Oligodontia-cancer predisposition syndrome' and 'Hereditary cancer-predisposing syndrome' - an adult-onset, variably penetrant polyposis/cancer predisposition phenotype, so the early-age full-penetrance precondition of BS2 is not satisfied.
No CSPEC or local AXIN2 framework exists (cspec.found=false; vcep_materials.json framework found=false, source=generic_acmg_fallback), so BS2 was evaluated under the generic ACMG/AMP 2015 definition with no gene-specific modification.
Still missing
Individual-level phenotype/health documentation for the gnomAD homozygote carriers is not available from gnomAD, so the homozygote observations cannot be adjudicated as BS2-compliant unaffected adults.
No penetrance estimate for AXIN2-associated oligodontia-colorectal cancer predisposition (in particular for a synonymous change) is available in the case materials, so the 'fully penetrant at an early age' precondition had to be assessed from the disease's known clinical character rather than from a quantitative penetrance figure.
No AXIN2 CSPEC/VCEP specification exists to define whether this framework would accept gnomAD homozygote counts as BS2 evidence at a reduced strength.
BS4Not met: no genotyped pedigree for c.1530G>A is reported, so non-segregation with disease in affected relatives has not been demonstrated.
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Reasoning
BS4 requires demonstrated lack of segregation of the variant with disease in affected members of a family (Richards et al. 2015, PMID:25741868). For NM_004655.4:c.1530G>A (p.(Thr510=)) there is no family in which genotype-phenotype tracking was performed at all, so non-segregation has neither been observed nor formally excluded. The single carrier fully described by PMID:16941501 had no reported family history of polyposis and no relatives were genotyped; PMID:29114927 and PMID:30555066 likewise report isolated carriers without pedigree analysis. The absence of affected relatives is not the same as observing the variant in an affected relative who cannot be explained by the genotype, which is what BS4 asks for. The variant's ClinVar aggregation as Benign/Likely benign across 19 submitters is a classification assertion, not segregation evidence, and was not substituted for a family study. BS4 is therefore not met, with the caveat that the underlying data are missing rather than contradicting.
Rule
ACMG/AMP 2015 BS4: lack of segregation in affected members of a family
Evidence considered
ACMG/AMP 2015 (PMID:25741868) defines BS4 as lack of segregation of the variant in affected family members.
PMID:16941501: the patient carrying c.1530G>A had no reported family history and no relatives were genotyped, so no segregation or non-segregation observation for this variant exists in that family.
PMID:29114927: isolated carrier among 37 unrelated patients; no pedigree genotyping.
PMID:30555066: isolated carrier; the paper classified all AXIN2 findings as common variants without any family analysis.
The ClinVar aggregate classification for variation 136481 was deliberately not used as a substitute for segregation evidence.
Still missing
No family study of c.1530G>A exists; non-segregation was never tested because no source genotyped affected relatives of the reported carriers.
BP2Not met: no pathogenic AXIN2 variant occurs in cis or trans; the only phased observation places c.1530G>A in cis with the non-pathogenic p.Asn412Ser (PMID:16941501).
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Reasoning
BP2 (Richards et al. 2015, PMID:25741868) is satisfied either by observing the variant in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or by observing it in cis with a pathogenic variant in any inheritance pattern; both routes require a pathogenic (or, in the usual laboratory extension, likely pathogenic) partner variant, with cis/trans status established by parental or other informative testing. No AXIN2 CSPEC/VCEP or local AXIN2 framework exists (cspec.found=false; vcep_materials.json source=generic_acmg_fallback), so the generic definition applies unchanged. No pathogenic or likely pathogenic AXIN2 variant is documented in trans with c.1530G>A anywhere in this case. The only phase-resolved observation of this variant is the cis configuration in PMID:16941501 (Table 2: c.[1235A>G (+) 1530G>A], p.[Asn412Ser (+) Thr510Thr], in an 18-year-old with 30 adenomatous polyps and no family history), and that cis partner is not a pathogenic variant: PolyPhen predicted p.Asn412Ser benign, no splicing effect was detected by RT-PCR, and the authors concluded both changes 'are likely to be polymorphisms', so the cis-with-a-pathogenic-variant route also fails. Population data show the variant in the homozygous state (gnomAD v2.1: 2 homozygotes, 806/282,518 alleles, AF 0.28529%, including 631/128,970 European non-Finnish with 2 homozygotes; gnomAD v4.1: 21 homozygotes, 7,188/1,613,744 alleles, AF 0.44542%; v3.1 non-cancer genomes: 1 homozygote), but homozygote counts in a population database are not part of the generic ACMG/AMP 2015 BP2 definition - they involve no pathogenic partner variant and, in the absence of individual-level phenotype documentation, do not establish a phase relationship to a pathogenic allele; no AXIN2 specification extends BP2 to that observation, and such population evidence is assessed by the benign-strength and population-frequency groups instead. BP2 is not met.
Rule
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
Generic ACMG/AMP 2015 BP2 definition applied verbatim (PMID:25741868): '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.' No AXIN2 CSPEC/VCEP or local framework exists (cspec.found=false; vcep_materials.json source=generic_acmg_fallback), so no gene-specific reweighting or additional BP2 trigger applies.
Cis/trans assessment: the only phase-resolved observation of this variant is PMID:16941501 Table 2, patient Li-9, c.[1235A>G (+) 1530G>A] / p.[Asn412Ser (+) Thr510Thr] - the two changes are on the same allele (cis), and the 18-year-old affected proband (30 adenomatous polyps, no family history of polyposis or colorectal cancer) is the only affected individual reported to carry this variant together with a second AXIN2 change.
Partner-variant pathogenicity check: the cis partner p.Asn412Ser is not a pathogenic variant - PolyPhen predicted it benign based on limited conservation of the Asn residue, RT-PCR from exons 3 to 7 showed the variants at a similar proportion as in genomic DNA (no splicing alteration), and the authors concluded 'these variations... are likely to be polymorphisms' (PMID:16941501). BP2 therefore cannot be applied on the cis route.
Absence of a trans observation: no source in this case (PMID:16941501, PMID:29114927, PMID:30555066) reports c.1530G>A in trans with a pathogenic or likely pathogenic AXIN2 variant, and no such second AXIN2 variant is recorded in the ClinVar submission audit (criteria_found and evidence_signals are empty for the audited submissions).
Population genotype check: gnomAD v2.1 (806/282,518 alleles, AF 0.28529%, 2 homozygotes; European non-Finnish 631/128,970 with 2 homozygotes) and gnomAD v4.1 (7,188/1,613,744 alleles, AF 0.44542%, 21 homozygotes; European non-Finnish 6,527/1,179,970 with 17 homozygotes) show the variant occurs in a homozygous state; gnomAD v3.1 non-cancer genomes report 1 homozygote (430/147,562 alleles) and gnomAD-Canada v1.0 reports 0 homozygotes (62/18,376 alleles). Each homozygote represents the same variant on both alleles, not a pathogenic variant in cis or trans, so these observations do not meet BP2's definition and are not counted here.
ClinVar record 136481 (Benign/Likely benign, 2 stars, 19 submissions) was not used to infer BP2, since a criterion may not be derived from another source's final classification.
Still missing
No pathogenic or likely pathogenic AXIN2 variant co-occurring with c.1530G>A in cis or trans is documented in any case source, so neither BP2 trigger could be evaluated positively.
The cis observation rests on a notation ('(+)') in Table 2 of PMID:16941501; no parental or independent phase testing is reported for the family, and the paper is inconsistent about the patient identifier for that genotype.
No AXIN2 CSPEC/VCEP exists that would define whether a homozygous population observation could be used for BP2 in this gene; the generic ACMG/AMP 2015 definition used here does not include such a clause.
BP5Not met: no alternate molecular basis is documented for the proband, and the variant's reported carrier was APC-, MMR- and MUTYH-negative.
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Reasoning
BP5 applies when the variant is found in a case that has an alternate molecular basis for the disease in question. This case provides no proband phenotype, no family history and no additional molecular findings, so no alternate genetic basis for the proband's disease is documented and the criterion cannot be satisfied from the case itself. The only individual reported with this exact variant and a detailed molecular workup is the polyposis patient in PMID:16941501: that patient was APC-mutation negative, MMR-defect negative, and is not among the MUTYH-mutated patients of that series (the patients with MUTYH changes are Li-1, Li-5, Li-7, Li-13, Li-15, Li-19, Li-22 and Li-31, and the c.1530G>A carrier is not among them); the authors instead concluded that both AXIN2 changes found in that patient were likely polymorphisms. In the other two variant-specific reports (PMID:29114927, PMID:30555066) the carriers are affected by non-syndromic tooth agenesis/hypodontia cohorts with no reported second molecular cause. No retrieved source reports this variant in a case whose phenotype is explained by a separate established molecular lesion. BP5 is therefore not met; the proband-level question remains answerable only if clinical data are supplied, which is flagged for review.
Rule
generic_acmg_BP5_alternate_molecular_basis (Richards et al. 2015, PMID:25741868); no AXIN2 VCEP/CSPEC rule available
Evidence considered
Generic ACMG/AMP 2015 BP5 definition (variant found in a case with an alternate molecular basis for disease; Richards et al. 2015, PMID:25741868) applied, as no ClinGen CSPEC/VCEP or local AXIN2 gene framework exists.
Case data contain no phenotype, family history or additional molecular findings for the individual tested (variant-only submission, NM_004655.4:c.1530G>A), so no alternate basis is documented for the proband.
PMID:16941501: the c.1530G>A carrier (patient Li-10 in the Results text; the same c.[1235A>G (+) 1530G>A] allele is listed under Li-9 in Table 2, and Table 1 shows that patient as APC-negative with 30 polyps) had no APC mutation and no MMR defect; that paper's MUTYH-mutated patients are Li-1, Li-5, Li-7, Li-13, Li-15, Li-19, Li-22 and Li-31, so the c.1530G>A carrier did not carry a biallelic MUTYH explanation either.
PMID:16941501: the authors concluded that the two AXIN2 changes in that patient were 'likely to be polymorphisms' and found no clearly pathogenic (frameshift or nonsense) AXIN2 mutation in any patient, so the reported case is not one in which an alternate molecular basis was established.
PMID:29114927 and PMID:30555066 report the same change in non-syndromic tooth agenesis/hypodontia cohorts without reporting a second, alternate molecular cause in the carriers.
Still missing
No proband phenotype or co-occurring molecular diagnosis is documented in the case data, so BP5 could not be evaluated at the individual-patient level; a human note on any alternate genetic cause (for example another variant explaining the phenotype) would close this gap.
For the reported literature carriers, alternate-basis status is only partially documented (APC, MMR and MUTYH results available in PMID:16941501; no alternate-cause screen reported for the tooth-agenesis cohorts).
BP6Not met: ClinVar's Benign/Likely benign label for this variant comes from 19 clinical laboratories with no expert-panel submission, which cannot trigger BP6.
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Reasoning
BP6 is applied here only for an exact-variant ClinVar classification issued by an expert panel (ClinGen VCEP/Expert Panel) asserting Benign or Likely benign; ordinary laboratory submissions, aggregate ClinVar labels and non-expert assertions must never trigger it. The exact-variant record NM_004655.4(AXIN2):c.1530G>A (p.Thr510=), VCV000136481 / ClinVarID 136481, is aggregate-labeled Benign/Likely benign with a 2-star review status ('criteria provided, multiple submitters, no conflicts'), but it contains 19 submissions from 19 ordinary clinical laboratories and zero expert-panel submissions (source_data.expert_panels empty; audit expert_panel_submissions = 0, is_expert_panel = false for every submission). Those submitter-level benign assertions - Benign from 8 clinical laboratories, Likely benign from 8 clinical laboratories, benign from 1 clinical laboratory - and the aggregate label are exactly the material this group's rule excludes from BP6, so the criterion is not met even though the direction of the ordinary-lab consensus is benign. No ClinGen CSPEC/VCEP specification exists for AXIN2, and the submission audit recorded no benign-criterion signal in the criterion-lead submissions (the only criterion signal captured anywhere in the audit is a PP3 in-silico signal), so no reputable-source expert assertion of benign status exists for this variant.
Rule
BP6_expert_panel_exact_variant_benign (ClinGen VCEP/Expert Panel only; aggregate ClinVar labels, ordinary laboratory submissions and non-expert assertions excluded); generic ACMG/AMP 2015 fallback since no AXIN2 specification exists
Evidence considered
Exact-variant ClinVar record NM_004655.4(AXIN2):c.1530G>A (p.Thr510=), VCV000136481 / ClinVarID 136481: 19 submissions, aggregate classification Benign/Likely benign, review status 'criteria provided, multiple submitters, no conflicts' (2 stars).
Expert-panel check on the exact record: source_data.expert_panels is empty and the submission audit reports expert_panel_submissions = 0 with is_expert_panel = false for all 19 submissions (submitters include Illumina Laboratory Services, University Medical Center Groningen, Sema4, Ambry Genetics, Quest Diagnostics, Labcorp/Invitae, University of Chicago, Kuwait Cancer Control Center, Rigshospitalet Copenhagen and Mayo Clinic Laboratories), i.e. no expert panel.
Submission breakdown: Benign (8 clinical laboratories), Likely benign (8 clinical laboratories), benign (1 clinical laboratory) - ordinary laboratory assertions that this group's rule for BP6 explicitly excludes, in addition to the aggregate ClinVar label.
No ClinGen CSPEC/VCEP exists for AXIN2 (CSPEC lookup found nothing; vcep_materials records 'no cspec url available'); the classification framework is the generic ACMG/AMP 2015 fallback.
No benign-criterion signal was recorded in the ClinVar submission criterion-lead audit: evidence_signals.criteria_found is empty for all submissions except a single PP3 in-silico signal, so no submission provided a distinct reputable-source benign assertion of the kind BP6 requires.
ACMG/AMP 2015 BP6 definition used as the generic fallback (Richards et al. 2015, PMID:25741868): reputable source reporting the variant as benign, with the group instruction restricting acceptance to an exact-variant expert-panel Benign/Likely benign classification.
Still missing
No ClinGen VCEP/Expert Panel has issued a Benign/Likely benign classification for this exact variant, and no AXIN2-specific expert specification exists; the ordinary-laboratory benign consensus cannot be counted under this group's rule.
PP4Not assessed: the case contains no proband phenotype, HPO terms or family history, so PP4's requirement for a phenotype highly specific to a single-gene disease cannot be evaluated.
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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. This case was submitted as a variant-only query (NM_004655.4:c.1530G>A, AXIN2): the case files contain no proband phenotype, no HPO terms, no family history, no clinical indication and no affected-relative information, so the premise of PP4 cannot be evaluated for this individual and the criterion is not assessed. The phenotype information that does exist is not this proband's phenotype: the ClinVar record's condition labels for the variant are aggregate submitter conditions ('Hereditary cancer-predisposing syndrome', 'Oligodontia-cancer predisposition syndrome', 'not provided', 'not specified'). For completeness, the retrieved variant-specific reports would not readily support phenotype specificity even if a proband phenotype were supplied: PMID:29114927 places the change in a non-syndromic tooth agenesis case-series (1 of 37 patients) and PMID:30555066 in a non-syndromic hypodontia cohort (1 of 60 patients), while PMID:16941501 places it in a patient with multiple adenomatous polyps and colorectal cancer risk, i.e. two unrelated phenotype domains rather than one disease that is highly specific for a single-gene etiology. The missing proband phenotype is flagged as the gap to close.
Rule
generic_acmg_PP4_phenotype_specificity (Richards et al. 2015, PMID:25741868); not evaluable because no proband phenotype is documented in this case
Evidence considered
Case data contain no clinical information for the individual being tested: review_manifest.json lists only a variant input (NM_004655.4:c.1530G>A) with no phenotype field, case_summary.json carries no HPO or indication field, and prefetch.json contains only normalization, population and in-silico steps.
Generic ACMG/AMP 2015 PP4 definition (patient's phenotype or family history highly specific for a disease with a single genetic etiology) applied, since no ClinGen CSPEC/VCEP or local AXIN2 framework exists (framework_complete=false, generic_acmg_fallback).
Phenotype evidence available in the case is record-level, not proband-level: ClinVar API conditions for VCV000136481 are 'Hereditary cancer-predisposing syndrome', 'Oligodontia-cancer predisposition syndrome', 'not provided' and 'not specified'.
PMID:29114927: the exact variant is reported in 1 of 37 patients with non-syndromic tooth agenesis (a cohort phenotype, not this proband's phenotype), with no clinical detail tying the phenotype specifically to this variant.
PMID:30555066: the same codon-510 synonymous change is reported in 1 of 60 patients with non-syndromic hypodontia; the authors treat it as a common variant, which also weakens any claim that the phenotype is highly specific to a single-gene cause.
PMID:16941501: the variant's carrier is a patient with multiple adenomatous polyps/colorectal cancer risk context, a different phenotype domain from the tooth-agenesis cohorts, so the retrieved reports do not describe one highly specific disease.
Still missing
No proband phenotype, HPO terms, family history or clinical indication are present anywhere in the case data (variant-only submission); a clinician-supplied phenotype is required before PP4 phenotype specificity can be judged.
Literature reports the same synonymous change in two unrelated phenotype domains (non-syndromic tooth agenesis/hypodontia and colorectal polyposis), so even with a proband phenotype the specificity premise would need explicit justification.
Not applicable · 10· 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.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). 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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PS1N/APS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1N/APM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
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.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). 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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PM5N/APM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2N/APP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP3N/ANot applicable: c.1530G>A is synonymous, p.(Thr510=), outside PP3's missense and intronic/splice-region scope.
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Reasoning
PP3 (Richards et al. 2015, PMID:25741868) applies here only to a missense variant, which is assessed through the REVEL protein-impact path, or to an intronic/splice-region variant, which is assessed through the SpliceAI path. NM_004655.4:c.1530G>A is neither: it is a synonymous substitution producing NP_004646.3:p.(Thr510=) in exon 6 of AXIN2, and the variant is not in a canonical splice region (the annotation most severe consequence is simply synonymous_variant, with no splice-region or splice-donor/acceptor annotation, and the SpliceAI model localises all of its (negligible) predicted events to positions 162-443 nucleotides away from the variant). Because the variant lies outside PP3's calibrated scope, PP3 is not applicable, and no REVEL, SpliceAI, VarSeak or BayesDel score was used to reach a PP3 verdict. No AXIN2 ClinGen VCEP/CSpec specification or gene-specific PP3/BP4 lookup table exists for this case (framework_mode = generic_acmg), so the generic ACMG/AMP 2015 scope rules apply.
Rule
requires_missense_or_intronic_splice_region
Evidence considered
Variant consequence: NM_004655.4:c.1530G>A is a synonymous substitution, predicted protein consequence NP_004646.3:p.(Thr510=), located in exon 6 of AXIN2.
The variant is annotated as synonymous_variant with no splice-region or splice-donor/acceptor annotation, so it is not a canonical splice-region or intronic variant.
No AXIN2 gene-specific VCEP/CSpec criteria specification or PP3/BP4 lookup spreadsheet is available (framework_mode = generic_acmg; cspec found = false), so the generic ACMG/AMP 2015 scope rules define which variant classes PP3 covers.
Scope decision precedes any predictor score: because the variant is not missense and not intronic/splice-region, no predictor result (REVEL, SpliceAI, VarSeak, BayesDel) was evaluated towards PP3.
BP1N/ABP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
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.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). 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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BP4N/ANot applicable: c.1530G>A is synonymous, p.(Thr510=), outside BP4's missense and intronic/splice-region scope.
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Reasoning
BP4 (Richards et al. 2015, PMID:25741868) applies here only to a missense variant, through the calibrated REVEL protein-impact path, or to an intronic/splice-region variant, through the SpliceAI splice path. NM_004655.4:c.1530G>A is a synonymous substitution (NP_004646.3:p.(Thr510=)) in exon 6 that is not a splice-region or intronic variant, so neither BP4 path applies to it. The computational evidence bearing on this variant - SpliceAI max delta 0.001 with no predicted acceptor or donor gain/loss - is the same single splice-prediction result that satisfies BP7, and it is scored once, under BP7, rather than being counted again as BP4; the variant therefore remains outside BP4's scope and BP4 is not applicable.
Rule
requires_missense_or_intronic_splice_region
Evidence considered
Variant consequence: NM_004655.4:c.1530G>A is a synonymous substitution, predicted protein consequence NP_004646.3:p.(Thr510=), exon 6 of AXIN2.
The missense protein-impact path is unavailable for this variant (REVEL returned no score, and a synonymous change has no amino-acid substitution to assess); the splice path is the only computational path in play, and the synonymous no-splice-impact determination is made under BP7.
No AXIN2 gene-specific VCEP/CSpec specification or gene-specific BP4 table exists for this case (framework_mode = generic_acmg).
Identifiers
Gene
AXIN2
Transcript
NM_004655.4
Coding (HGVS c.)
NM_004655.4:c.1530G>A
Protein (HGVS p.)
NP_004646.3:p.(Thr510=)
GRCh38
chr17:65537506 C>T
GRCh37
chr17:63533624 C>T
Location and type
Exon 6 · synonymous
ClinVar
136481
COSMIC
COSV104596682
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
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Transcript span
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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 0.0045 · 7188 / 1,613,744 alleles · 21 hom · FAF 0.0054
European (non-Finnish)6527 / 1,179,970
0.005517 hom
Remaining individuals290 / 62,508
0.00462 hom
Middle Eastern16 / 6,058
0.00261 hom
Admixed American147 / 60,014
0.0024
South Asian85 / 91,074
0.000931 hom
African/African American67 / 74,966
0.00089
European (Finnish)50 / 63,918
0.00078
Ashkenazi Jewish6 / 29,606
0.0002
0 alternate alleles recorded in 2 other groups: Amish, East Asian.
gnomAD v2.1
AF 0.0029 · 806 / 282,518 alleles · 2 hom · FAF 0.0047
European (non-Finnish)631 / 128,970
0.00492 hom
Remaining individuals24 / 7,220
0.0033
Admixed American86 / 35,434
0.0024
African/African American25 / 24,930
0.001
South Asian28 / 30,616
0.00091
European (Finnish)11 / 25,040
0.00044
Ashkenazi Jewish1 / 10,364
9.6e-05
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00445424; MAF= 0.44542%, 7188/1613744 alleles, homozygotes = 21) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0055315; MAF= 0.55315%, 6527/1179970 alleles, homozygotes = 17); grpmax FAF= 0.00541925.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00285292; MAF= 0.28529%, 806/282518 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00489261; MAF= 0.48926%, 631/128970 alleles, homozygotes = 2); grpmax FAF= 0.0047191.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0033739660426643447, 62/18376 alleles, homozygotes = 0).
BP7SupportingMet, supporting: synonymous p.(Thr510=) with SpliceAI max delta 0.001, far below the 0.2 significant-impact cutoff.
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Reasoning
BP7 (Richards et al. 2015, PMID:25741868) applies to a synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and no creation of a new splice site. NM_004655.4:c.1530G>A is synonymous (NP_004646.3:p.(Thr510=)). SpliceAI returns DS_AG 0.001, DS_AL 0.001, DS_DG 0.00 and DS_DL 0.00, giving a maximum delta score of 0.001, and Pangolin gives splice-gain 0.002 / splice-loss -0.001; no cryptic acceptor or donor site is predicted. These values sit far below the SpliceAI recommended cutoff of 0.2 for significant splice impact (Jaganathan et al. 2019, PMID:30661751) and below the 0.1 no-impact level, so the predicted-splice-silence requirement is met. Independent experimental corroboration exists for this exact variant: transcript analysis by RT-PCR in a patient carrying c.1530G>A showed the variant present in the amplified cDNA at the same proportion as in genomic DNA, indicating no splicing alteration (Lejeune et al. 2006, PMID:16941501), and the same variant has since been reported as a synonymous/common finding in tooth-agenesis cohorts (PMID:29114927, PMID:30555066) without any demonstration of a splice effect. BP7 is therefore met at supporting strength. A quantitative nucleotide-conservation metric (e.g. phyloP/GERP) for this position was not available in the evidence reviewed; the position is not annotated as conserved, and the variant's appreciable population frequency in gnomAD v4.1 (AF 0.445%, 21 homozygotes) plus the concordant negative splice predictions and the negative RT-PCR result make a constrained, functionally relevant nucleotide at this position unlikely.
The variant is synonymous: NM_004655.4:c.1530G>A, NP_004646.3:p.(Thr510=), exon 6 of AXIN2.
SpliceAI scores for NM_004655.4:c.1530G>A are DS_AG 0.001, DS_AL 0.001, DS_DG 0.00, DS_DL 0.00; maximum delta score is 0.001, i.e. no predicted splice-acceptor or splice-donor gain or loss.
Pangolin scores for the same variant are splice-gain 0.002 and splice-loss -0.001, concordant with no predicted splice impact.
The SpliceAI recommended cutoff for significant splice impact is 0.2 (Jaganathan et al. 2019, PMID:30661751); the observed maximum delta of 0.001 is far below it and below the 0.1 no-impact level.
Lejeune et al. 2006 (PMID:16941501) performed RT-PCR on transcripts of a patient carrying this exact variant using primers within exons 3 and 7 and found the variant present at a similar proportion as in genomic DNA, indicating no splicing alteration; the variant was reported as an apparently silent change and the authors considered it likely to be a polymorphism.
PMID:29114927 reported this synonymous variant in 1/37 patients with non-syndromic tooth agenesis and noted that a splice-site effect should be considered, but presented no functional or transcript data showing any splice effect.
PMID:30555066 listed the codon-510 synonymous change (written as c.1531G>A, Thr510Thr, rs63533624 in that paper) among AXIN2 variants and classified all AXIN2 findings as common variants.
ClinVar (variation 136481) holds only Benign/Likely benign assertions for this variant (multiple clinical laboratories, no expert-panel submission), consistent with a benign synonymous change rather than a splice-altering one.
gnomAD v4.1 reports this variant at AF 0.445% (7188/1613744 alleles) with 21 homozygotes, and gnomAD v2.1 at AF 0.285% with 2 homozygotes, arguing against a highly constrained nucleotide position.
No AXIN2 gene-specific VCEP/CSpec specification or BP7 lookup table exists for this case (framework_mode = generic_acmg), so the generic ACMG/AMP 2015 BP7 definition with published SpliceAI thresholds was applied.
Still missing
No quantitative nucleotide-conservation metric (phyloP/GERP/phastCons) for the c.1530 position was present in the evidence reviewed; the no-splice-impact requirement of BP7 is nevertheless supported concordantly by SpliceAI, Pangolin and an independent patient RT-PCR study.
PP3N/ANot applicable: c.1530G>A is synonymous, p.(Thr510=), outside PP3's missense and intronic/splice-region scope.
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Reasoning
PP3 (Richards et al. 2015, PMID:25741868) applies here only to a missense variant, which is assessed through the REVEL protein-impact path, or to an intronic/splice-region variant, which is assessed through the SpliceAI path. NM_004655.4:c.1530G>A is neither: it is a synonymous substitution producing NP_004646.3:p.(Thr510=) in exon 6 of AXIN2, and the variant is not in a canonical splice region (the annotation most severe consequence is simply synonymous_variant, with no splice-region or splice-donor/acceptor annotation, and the SpliceAI model localises all of its (negligible) predicted events to positions 162-443 nucleotides away from the variant). Because the variant lies outside PP3's calibrated scope, PP3 is not applicable, and no REVEL, SpliceAI, VarSeak or BayesDel score was used to reach a PP3 verdict. No AXIN2 ClinGen VCEP/CSpec specification or gene-specific PP3/BP4 lookup table exists for this case (framework_mode = generic_acmg), so the generic ACMG/AMP 2015 scope rules apply.
Rule
requires_missense_or_intronic_splice_region
Evidence considered
Variant consequence: NM_004655.4:c.1530G>A is a synonymous substitution, predicted protein consequence NP_004646.3:p.(Thr510=), located in exon 6 of AXIN2.
The variant is annotated as synonymous_variant with no splice-region or splice-donor/acceptor annotation, so it is not a canonical splice-region or intronic variant.
No AXIN2 gene-specific VCEP/CSpec criteria specification or PP3/BP4 lookup spreadsheet is available (framework_mode = generic_acmg; cspec found = false), so the generic ACMG/AMP 2015 scope rules define which variant classes PP3 covers.
Scope decision precedes any predictor score: because the variant is not missense and not intronic/splice-region, no predictor result (REVEL, SpliceAI, VarSeak, BayesDel) was evaluated towards PP3.
BP4N/ANot applicable: c.1530G>A is synonymous, p.(Thr510=), outside BP4's missense and intronic/splice-region scope.
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Reasoning
BP4 (Richards et al. 2015, PMID:25741868) applies here only to a missense variant, through the calibrated REVEL protein-impact path, or to an intronic/splice-region variant, through the SpliceAI splice path. NM_004655.4:c.1530G>A is a synonymous substitution (NP_004646.3:p.(Thr510=)) in exon 6 that is not a splice-region or intronic variant, so neither BP4 path applies to it. The computational evidence bearing on this variant - SpliceAI max delta 0.001 with no predicted acceptor or donor gain/loss - is the same single splice-prediction result that satisfies BP7, and it is scored once, under BP7, rather than being counted again as BP4; the variant therefore remains outside BP4's scope and BP4 is not applicable.
Rule
requires_missense_or_intronic_splice_region
Evidence considered
Variant consequence: NM_004655.4:c.1530G>A is a synonymous substitution, predicted protein consequence NP_004646.3:p.(Thr510=), exon 6 of AXIN2.
The missense protein-impact path is unavailable for this variant (REVEL returned no score, and a synonymous change has no amino-acid substitution to assess); the splice path is the only computational path in play, and the synonymous no-splice-impact determination is made under BP7.
No AXIN2 gene-specific VCEP/CSpec specification or gene-specific BP4 table exists for this case (framework_mode = generic_acmg).
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
7 paper records listed. 4 cited in the classification.
Cited in the classification
Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis.
Lejeune S et al. · 2006 Oct
Lejeune et al. screened AXIN2 by PCR/direct sequencing in 31 unrelated patients with multiple adenomatous polyps or colorectal cancer without APC mutation or MMR defect. The exact variant c.1530G>A (p.Thr510Thr) was found in one patient (Li-10 in the Results; listed under Li-9 in Table 2) aged 18 with 30 adenomatous polyps and no family history, in cis with the missense change c.1235A>G (p.Asn412Ser). This is the only source that both detected the variant in a patient and examined that patient's family context, and its methods state that parental DNA samples were not available; no parental genotyping, de novo claim, pedigree, meiosis count or LOD score is reported for this variant. The authors interpreted both changes as likely polymorphisms.
→ BS3 · supporting→ BP7 · supportingNames this variant
Confirmation of biallelic mutations. In absence of parents DNA samples, allele-specific PCR (AS-PCR) was performed in cases where two mutations were found in order to assess if the variations were present on the same allele or on different alleles.
Location Materials and Methods, 'Confirmation of biallelic mutations'; carrier and variant described in Results, 'AXIN2 Gene Analysis' paragraph 1 and Table 2
Context Germline screening of AXIN2 (NM_004655.2, exons 1-10 plus exon-intron boundaries) by PCR and direct sequencing in 31 unrelated polyposis/CRC patients without APC mutation or MMR defect; RT-PCR across exons 3-7 to test splicing in the carrier; 50 healthy controls screened for the variant.
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
ACMG/AMP 2015 standards and guidelines for sequence variant interpretation; the source of the PS2, PM6, PP1 and BS4 criteria definitions applied here. It specifies that a de novo variant with negative parental samples and identity-confirmed parentage qualifies for strong pathogenic support (PS2), that PM6 applies where parentage is assumed but not confirmed, that PP1 is co-segregation with disease in multiple affected family members, and that BS4 is lack of segregation in affected family members. It does not mention AXIN2 or c.1530G>A.
→ BS3 · supporting→ BP7 · supportingDoes not name this variant
A variant observed to have arisen de novo (parental samples test negative), is considered strong support for pathogenicity if the following conditions are met: Both parental samples were shown through identity testing to be the biological parents of the patient. Note: PM6 applies if identity is assumed but not confirmed.
Location Section 'PS2 PM6 De novo variants' (criterion definitions and de novo conditions)
Context Consensus guideline document (ACMG/AMP joint recommendation); no experimental data, cohorts or pedigrees. Used as the governing criterion definitions in the absence of any AXIN2-specific CSPEC/VCEP framework.
Genetic study of non-syndromic tooth agenesis through the screening of paired box 9, msh homeobox 1, axin 2, and Wnt family member 10A genes: a case-series.
Haddaji Mastouri M et al. · 2018 Feb
Haddaji Mastouri et al. sequenced AXIN2, PAX9, MSX1 and WNT10A in 37 Tunisian patients with non-syndromic tooth agenesis (28 sporadic, 9 familial) plus 88 healthy dentate controls. The synonymous AXIN2 change p.Thr510Thr (rs141014640) was found in 1 of 37 patients (2.7%), with very low population frequencies (0.001 in the African population, 0 in the European population). The authors did not attribute a pathogenic role to it, noted only that a splice-site effect should be considered because of its rarity, and did not include it among the variants highlighted as probably disease-causing or in their case-control association analysis. No parental testing, co-segregation analysis or meiosis data for this variant were reported, despite the cohort containing 9 familial cases.
According to the allele frequencies (Table 1) only one silent variant (p.Thr510Thr, rs141014640) was less frequent in the African population as well as in the European population (0.001(A), 0 (A)). A splice-site change should be considered.
Context Case-series cohort of 37 non-syndromic tooth-agenesis patients (28 sporadic, 9 familial) and 88 healthy dentate controls; Sanger sequencing of coding exons and exon-intron boundaries of AXIN2, PAX9, MSX1 and WNT10A; allele frequencies compared with ExAC/Ensembl and case-control analysis by chi-square.
WNT10A variants in relation to nonsyndromic hypodontia in eastern Slovak population.
Grejtakova D et al. · 2018 Dec
Grejtakova et al. Sanger-sequenced WNT10A, PAX9 and AXIN2 in 60 unrelated eastern Slovak patients with non-syndromic hypodontia and 48 controls. A codon-510 synonymous AXIN2 change (Thr510Thr, rs63533624) was detected in a single patient and counted among six synonymous AXIN2 variants; the AXIN2 findings were classified as common variants and excluded from further association analysis. No parental testing, segregation analysis or family genotyping was performed for this change. Note the numbering discrepancy: the paper writes c.1531G>A for the same protein change (p.Thr510Thr) annotated as c.1530G>A in the queried transcript, i.e. the same codon-510 synonymous change.
Context Sanger sequencing of all exons, exon/intron junctions and UTRs of WNT10A, PAX9 and AXIN2 in 60 unrelated Caucasian patients of eastern Slovak origin with non-syndromic hypodontia (37 maxillary lateral incisor agenesis cases) plus 48 healthy controls; reference sequence NC_000017.10.
Other recorded publications
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
Karbassi I et al. · 2016
Karbassi et al. describe a CLIA laboratory's rules-based, weighted variant pathogenicity scoring system built on ACMG/AMP categories, including how family segregation evidence is quantified: LOD scores estimated from the number of meiotic events, additional weight for confirmed de novo variants and partial weight for unconfirmed de novo events. It contains no AXIN2- or variant-specific data; its only relevant observation for a synonymous change such as p.(T510=) is aggregate behaviour (about 1% of synonymous variants scored in the pathogenic range). It was consulted to frame how segregation/de novo evidence is weighted, and contributed no criterion-level evidence for this variant.
The segregation of variants in family pedigrees was analyzed by estimating the logarithm of the odds (LOD) score or by a statistical association test if the family data were incomplete. The LOD score was estimated based on the number of meiotic events and weighted as evidence for the segregation between the disease locus and the variant in family pedigrees.
Methods, 'Variant segregation analysis in families'
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
ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. It covers referral criteria for recognised hereditary cancer syndromes by tumour type and names only FLCN, PRKAR1A, MLH1, MSH2, MSH6 and PMS2 in the supplied text; it does not mention AXIN2 and says nothing about c.1530G>A, de novo occurrence, segregation or non-segregation. It was reviewed because ClinVar submissions for this variant cite it, and it provided no evidence for any criterion in this group.
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= 0.00445424; MAF= 0.44542%, 7188/1613744 alleles, homozygotes = 21) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0055315; MAF= 0.55315%, 6527/1179970 alleles, homozygotes = 17); grpmax FAF= 0.00541925.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00285292; MAF= 0.28529%, 806/282518 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00489261; MAF= 0.48926%, 631/128970 alleles, homozygotes = 2); grpmax FAF= 0.0047191.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0033739660426643447, 62/18376 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (8 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 136481)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104596682, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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