Variant classification summary

NM_001128425.2:c.309G>A

MUTYH · NP_001121897.1:p.(Trp103Ter) · NM_001128425.2

GRCh37: chr1:45799124 C>T · GRCh38: chr1:45333452 C>T

Gene: MUTYH Transcript: NM_001128425.2

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Trp103Ter)

gnomAD AF

2.7879279004672568e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 (very strong) supports a loss-of-function effect from the early p.Trp103Ter truncation.

2

Likely Pathogenic: PM2 (supporting) is met because the maximum gnomAD population frequency is below 0.0001.

Final determination: The incomplete MUTYH framework requires the generic ACMG/AMP fallback, and the deterministic derivation assigns Likely Pathogenic to the applied combination of PVS1 very strong plus PM2 supporting.

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	Met	Met at very strong: nonsense p.Trp103Ter truncates the 550-amino-acid MUTYH protein at residue 103, with no evidence of a downgrade-triggering NMD escape or distal non-critical region.	cspec pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented parental genotypes or confirmed de novo occurrence is available for the affected proband.	cspec
PS3	Not assessed	Not assessed: no validated functional assay directly tested MUTYH c.309G>A (p.Trp103Ter), so PS3 strength cannot be calibrated from the available evidence.	cspec PMID:23108399
PS4	Not assessed	Not assessed: the available 302-person cohort report lacks exact-variant case counts, controls, enrichment, odds ratio, or statistical significance for NM_001128425.2:c.309G>A.
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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: gnomAD v4.1 maximum population AF 3.8134e-05 is below the 0.0001 PM2 threshold.	cspec gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband genotype, second pathogenic MUTYH allele, or phase information is documented to evaluate biallelic inheritance.	cspec
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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); 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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no apparently de novo proband observation or parental-testing context is reported for this variant.	cspec
PP1	Not assessed	Not assessed: no informative relatives, segregating meioses, or genotype–phenotype co-segregation data are reported.	cspec
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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the variant is a nonsense change producing p.(Trp103Ter), outside PP3's calibrated computational-evidence scope.	cspec
PP4	Not assessed	Not assessed: no patient phenotype or phenotype-specific clinical features are provided to establish a match with MUTYH-associated polyposis.
PP5	Not met	Not met: ClinVar has 12 Pathogenic and one Likely pathogenic laboratory assertions, but zero exact-variant expert-panel submissions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum population AF 3.8134e-05 is far below the 0.05 BA1 threshold.	cspec gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 maximum population AF 3.8134e-05 is below the generic 0.01 BS1 threshold.	cspec gnomad_v4
BS2	Not met	Not met: gnomAD reports 0 homozygotes, so no unaffected-homozygote observation supports BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign functional assay directly tested MUTYH c.309G>A (p.Trp103Ter) or demonstrated preserved function.	cspec PMID:23108399
BS4	Not assessed	Not assessed: no unaffected carrier with adequate phenotype and age information is documented to demonstrate non-segregation.	cspec
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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no same-individual co-occurrence with a pathogenic variant and no cis/trans phase information are documented for BP2.
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_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant is a nonsense change producing p.(Trp103Ter), so the SpliceAI score 0.174 is outside BP4's scope.	cspec
BP5	Not assessed	Not assessed: no alternate pathogenic cause, second disease-causing variant, or relevant co-occurrence evidence is documented.
BP6	Not met	Not met: the exact-match ClinVar audit reports zero expert-panel submissions and no Benign or Likely benign expert-panel classification.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001128425.2:c.309G>A in MUTYH is a nonsense substitution introducing a premature stop codon predicted to produce NP_001121897.1:p.(Trp103Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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