LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-14
Case ID: NM_001128425.2_c.925C_T_20260914_202933
Framework: ACMG/AMP 2015
Variant classification summary

NM_001128425.2:c.925C>T

MUTYH  · NP_001121897.1:p.(Arg309Cys)  · NM_001128425.2
GRCh37: chr1:45797846 G>A  ·  GRCh38: chr1:45332174 G>A
Gene: MUTYH Transcript: NM_001128425.2
Final call
VUS
PS3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MUTYH
Transcript
NM_001128425.2
Protein
NP_001121897.1:p.(Arg309Cys)
gnomAD AF
0.0006944599319540776 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: PS3 supporting was assigned because p.Arg309Cys was partially defective in a controlled complementation assay, but this alone is insufficient for a definitive classification.
Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not satisfy any pathogenic, likely pathogenic, likely benign, or benign combination, so the final call 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.925C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg309Cys). 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 met Not met: no pathogenic alternate nucleotide change producing the same p.Arg309Cys substitution was identified.
cspec PMID:25820570 PMID:19032956 PMID:22297469
PS2 Not assessed Not assessed: no documented affected proband with confirmed parental genotypes and proven de novo occurrence is available for PS2 evaluation.
cspec
PS3 Met Met at supporting: p.R309C was partially defective in a controlled MutY-deficient E. coli assay using the 1.7-fold partial-defect threshold.
cspec PMID:25820570
PS4 Not assessed Not assessed: p.R309C lacks a validated PS4 case-control enrichment statistic or applicable MUTYH-specific threshold.
cspec PMID:19032956 PMID:22297469
PM1 Not assessed Not assessed: the MUTYH specification provides no retrieved authoritative domain table to verify whether residue 309 lies in an approved critical domain.
cspec PMID:16557584 PMID:20848659
PM2 Not met Not met: gnomAD v4.1 total allele frequency is 0.00069446, exceeding the generic PM2 threshold of 0.0001.
cspec gnomad_v4 gnomad_v2 PMID:25741868
PM3 Not assessed Not assessed: c.925C>T was reported once in a MAP cohort, but the partner allele and cis/trans phase were not documented.
cspec PMID:19032956 PMID:16557584 generic_acmg_combination_rules
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.925C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg309Cys). 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 pathogenic alternate missense variant at MUTYH residue Arg309 was established in the available evidence.
cspec PMID:19032956 PMID:25820570 PMID:22297469
PM6 Not assessed Not assessed: no unconfirmed de novo occurrence in a clinically characterized proband is documented for PM6.
PP1 Not assessed Not assessed: no informative affected-relative segregation series or count of concordant meioses is reported for p.Arg309Cys.
PMID:19032956 PMID:22297469 cspec
PP2 Not assessed Not assessed: no MUTYH-specific evidence establishes the required combination of common pathogenic missense variation and rare benign missense variation.
cspec PMID:16557584 PMID:19032956 PMID:25820570
PP3 Not met Not met: REVEL 0.592 is below the PP3 supporting threshold of 0.644, while SpliceAI is unavailable and BayesDel lacks a calibrated generic cutoff.
cspec revel spliceai bayesdel
PP4 Not assessed Not assessed: reported colorectal phenotypes are not sufficiently specific, and no MUTYH-specific PP4 phenotype rule was available.
cspec PMID:19032956 PMID:22297469
PP5 Not assessed Not assessed: ClinVar reports zero exact-variant expert-panel submissions supporting Pathogenic or Likely pathogenic.
clinvar
BA1 Not met Not met: gnomAD v4.1 allele frequency is 0.00069446, far below the generic BA1 stand-alone threshold of 0.05.
cspec gnomad_v4 gnomad_v2 PMID:25741868
BS1 Not met Not met: the highest observed gnomAD v4.1 population frequency is 0.000883025, below the generic BS1 threshold of 0.01.
cspec gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: gnomAD v4.1 has one homozygote, but its clinical unaffected status is unavailable for the BS2 requirement.
cspec gnomad_v4 gnomad_v2
BS3 Not met Not met: prior normal glycosylase activity conflicts with the exact-variant complementation result showing partial dysfunction at the 1.7-fold threshold.
cspec PMID:25820570 PMID:22297469
BS4 Not assessed Not assessed: no well-phenotyped affected relatives shown to lack p.Arg309Cys in an informative family are documented.
PMID:19032956 PMID:22297469
BP1 Not assessed Not assessed: available MUTYH evidence does not establish the gene-level truncating-predominance pattern required for BP1.
cspec PMID:16557584 PMID:19032956 PMID:25820570
BP2 Not assessed Not assessed: c.925C>T was observed in heterozygous controls, but no pathogenic partner allele or trans phase was documented.
cspec PMID:22297469 generic_acmg_combination_rules
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.925C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg309Cys). 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 0.592 exceeds the BP4 supporting threshold of 0.29, while SpliceAI is unavailable and BayesDel lacks a calibrated generic cutoff.
cspec revel spliceai bayesdel
BP5 Not assessed Not assessed: no validated BP5 alternative-molecular-diagnosis evidence or MUTYH-specific threshold was available.
cspec PMID:19032956 PMID:22297469
BP6 Not assessed Not assessed: ClinVar reports zero exact-variant expert-panel submissions supporting 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.925C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg309Cys). 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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