Variant classification summary

NM_004655.4:c.1365A>T

AXIN2 · NP_004646.3:p.(Pro455=) · NM_004655.4

GRCh37: chr17:63533789 T>A · GRCh38: chr17:65537671 T>A

Gene: AXIN2 Transcript: NM_004655.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

AXIN2

Transcript

NM_004655.4

Protein

NP_004646.3:p.(Pro455=)

gnomAD AF

0.0 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1 (0 of 1,559,354 alleles).

2

VUS: BP4 supporting is met because the synonymous change has a SpliceAI maximum delta of 0.001, below the 0.1 no-impact cutoff.

3

VUS: no pathogenic criterion is met and the only benign criterion met is BP4 supporting, so no combination rule for Benign, Likely Benign, Likely Pathogenic or Pathogenic is reached.

Final determination: Under the generic ACMG/AMP 2015 fallback, the combination of one supporting pathogenic criterion (PM2) with one supporting benign criterion (BP4) matches no pathogenic, likely pathogenic, benign or likely benign combination rule and therefore yields Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004655.4:c.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (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.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). 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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype and zero parental genotypes in the case, so a confirmed de novo occurrence can be neither shown nor excluded.	generic_acmg_combination_rules clinvar
PS3	Not met	Not met: no functional assay of AXIN2 c.1365A>T (p.Pro455=) exists in any consulted source, so damaging-effect evidence is absent.	generic_acmg_combination_rules PMID:25394175 oncokb clinvar
PS4	Not met	Not met: no case-control or affected-cohort enrichment data exists for this variant, which is absent from gnomAD v4.1 (0/1,559,354 alleles).	clinvar gnomad_v2 gnomad_v4 PMID:25394175 generic_acmg_combination_rules
PM1	N/A	PM1 (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.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). 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.	generic_acmg_combination_rules
PM2	Met	Met at supporting: variant is absent from gnomAD v4.1 (0/1,559,354 alleles), below the 0.0001 PM2 threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: PM3 is restricted to recessive disorders while AXIN2 disease is dominant, and no pathogenic variant was reported in trans.	clinvar generic_acmg_combination_rules PMID:25394175
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004655.4:c.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (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.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). 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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband phenotype and no parental testing status is recorded, so an assumed de novo occurrence cannot be evaluated.	generic_acmg_combination_rules clinvar
PP1	Not assessed	Not assessed: zero pedigrees and zero genotyped relatives are available, so co-segregation and its informative meiosis count cannot be evaluated.	generic_acmg_combination_rules clinvar
PP2	N/A	PP2 (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.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). 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.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.001 is far below the >=0.2 PP3 supporting cutoff for this synonymous variant, which is scored on the splice path only.	spliceai generic_acmg_combination_rules final_classification_framework
PP4	Not assessed	Not assessed: no proband phenotype or family history was available to test specificity for a single-gene AXIN2 phenotype.	clinvar PMID:25394175 generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar has four exact-variant submissions, none from an expert panel, with only a 2-star aggregate label.	clinvar PMID:28492532 PMID:25394175 generic_acmg_combination_rules
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 0 (0/1,559,354 alleles), far below the 0.05 stand-alone benign threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: gnomAD v4.1 allele frequency is 0 (0/1,559,354 alleles), far below the 0.01 strong benign threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: gnomAD v4.1 homozygote count is 0 and allele count is 0/1,559,354, so no healthy-adult carrier was observed.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not met	Not met: no functional assay of AXIN2 c.1365A>T exists; SpliceAI max delta 0.001 is computational, not assay evidence of normal function.	generic_acmg_combination_rules spliceai clinvar
BS4	Not assessed	Not assessed: no affected relatives are genotyped, so non-segregation cannot be demonstrated; ClinVar's benign assertions are not family-level evidence.	generic_acmg_combination_rules clinvar
BP1	N/A	BP1 (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.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). 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.	generic_acmg_combination_rules
BP2	Not met	Not met: neither the four ClinVar submissions nor the case literature report c.1365A>T in cis or in trans with a pathogenic variant.	clinvar generic_acmg_combination_rules PMID:25394175 PMID:28492532
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004655.4:c.1365A>T in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Pro455=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: SpliceAI max delta 0.001 is at or below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.	spliceai generic_acmg_combination_rules final_classification_framework
BP5	Not assessed	Not assessed: no proband-level molecular data was available to identify an alternate molecular basis for disease.	clinvar generic_acmg_combination_rules
BP6	Not met	Not met: no expert-panel classification exists for this exact variant; all four ClinVar submissions are ordinary clinical laboratories (2 stars).	clinvar PMID:28492532 generic_acmg_combination_rules
BP7	Not met	Not met: this synonymous variant's only supporting result, SpliceAI max delta 0.001, is already credited under BP4, and no conservation data is available.	spliceai generic_acmg_combination_rules final_classification_framework

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.