NM_001128425.2:c.505G>A

MUTYH · NP_001121897.1:p.(Glu169Lys) · NM_001128425.2

GRCh37: chr1:45798506 C>T · GRCh38: chr1:45332834 C>T

Gene: MUTYH Transcript: NM_001128425.2

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Glu169Lys)

gnomAD AF

6.194911747287248e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: gnomAD v4.1 total allele frequency is 6.19e-7, below 0.0001.

PP3 moderate: REVEL 0.846 exceeds the calibrated moderate threshold of 0.773.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one moderate criterion plus one supporting criterion does not satisfy a pathogenic, likely pathogenic, likely benign, or benign combination, so the result is VUS.

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_001128425.2:c.505G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Glu169Lys). 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; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic p.Glu169Lys comparator was identified, and ClinVar classifies the target variant as uncertain significance.	clinvar cspec
PS2	Not assessed	Not assessed: no documented parental genotypes or confirmed de novo observation is available for MUTYH c.505G>A.	cspec
PS3	Not assessed	Not assessed: no validated variant-specific functional assay or damaging biological readout was identified for p.Glu169Lys.	cspec
PS4	Not assessed	Not assessed: no exact-variant case-control counts or enrichment metric such as an odds ratio, relative risk, or p-value is available.	cspec PMID:24310308 PMID:25452455
PM1	Not assessed	Not assessed: no approved MUTYH domain entry or statistically significant hotspot places residue 169 in a critical region.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 6.19e-7, below the 0.0001 PM2 threshold, with zero homozygotes.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation or phase-resolved second MUTYH variant is documented, so PM3 cannot be assigned.	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.505G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Glu169Lys). 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	Not assessed	Not assessed: no validated pathogenic or likely pathogenic alternate missense variant at MUTYH residue 169 was identified.	clinvar cspec
PM6	Not assessed	Not assessed: no publication or case record reports c.505G>A as presumed de novo without parental testing.
PP1	Not assessed	Not assessed: no affected relatives, parental phase, biallelic genotypes, or informative meioses are reported for segregation analysis.	cspec
PP2	Not assessed	Not assessed: no validated MUTYH missense-enrichment estimate or applicable PP2 rule is available.	cspec oncokb
PP3	Met	Met (moderate): REVEL 0.846 meets the published PP3 moderate threshold of >=0.773.	revel cspec
PP4	Not assessed	Not assessed: no patient phenotype, polyp burden, cancer history, or family history is documented to compare with MUTYH-associated polyposis.	cspec PMID:25394175 PMID:25452455
PP5	Not met	Not met: exact-variant ClinVar classification is Uncertain significance with 0 expert-panel submissions, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total AF is 6.19e-7, far below the 0.05 BA1 stand-alone threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest gnomAD v4.1 subpopulation AF is 1.60e-5, below the generic 0.01 BS1 threshold.	cspec gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes, so no unaffected biallelic individual supports recessive BS2.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no validated variant-specific functional assay or normal biological readout was identified for p.Glu169Lys.	cspec
BS4	Not assessed	Not assessed: no tested relatives or phenotype-genotype comparisons are available to evaluate non-segregation.
BP1	Not assessed	Not assessed: no validated evidence shows that MUTYH disease is predominantly caused by truncating rather than missense variants.	cspec oncokb
BP2	Not assessed	Not assessed: no validated cis/trans relationship between c.505G>A and another pathogenic variant is documented for a benign-evidence determination.	cspec
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.505G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Glu169Lys). 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	Not met	Not met: REVEL 0.846 exceeds the highest applicable BP4 threshold of <=0.29.	revel cspec
BP5	Not assessed	Not assessed: no patient phenotype or well-established alternate molecular diagnosis is available to support BP5.
BP6	Not met	Not met: exact-variant ClinVar classification is Uncertain significance with 0 expert-panel submissions, not Benign or Likely benign.	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.505G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Glu169Lys). 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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