LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-01
Case ID: NM_001128425.2_c.1276C_T_20261001_164803
Framework: ACMG/AMP 2015
Variant classification summary

NM_001128425.2:c.1276C>T

MUTYH  · NP_001121897.1:p.(Arg426Cys)  · NM_001128425.2
GRCh37: chr1:45797139 G>A  ·  GRCh38: chr1:45331467 G>A
Gene: MUTYH Transcript: NM_001128425.2
Final call
VUS
BS3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MUTYH
Transcript
NM_001128425.2
Protein
NP_001121897.1:p.(Arg426Cys)
gnomAD AF
0.0013085031640746492 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS3 (supporting) met: the calibrated E. coli base-excision-repair complementation assay classified p.Arg426Cys as functionally retained, below its 1.7-fold retained cutoff.
2
No pathogenic criterion met: PS1, PS3 and PM5 find no established pathogenic comparator at codon 426, PP3 is indeterminate (REVEL 0.615) and PM2 fails because gnomAD frequencies (up to 0.00167) exceed the 0.0001 rarity threshold.
3
No benign-frequency criterion met: BA1 (0.05) and BS1 (0.01) both fail, with the highest observed population frequency about 30-fold and 6-fold below their thresholds.
Final determination: Under the generic ACMG/AMP 2015 combination rules, one supporting benign criterion (BS3) with no pathogenic criteria satisfies neither Likely Benign (requires one strong plus one supporting benign, or two supporting benign) nor any pathogenic combination, so the variant is classified as 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_001128425.2:c.1276C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg426Cys). 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 second nucleotide change encoding p.Arg426Cys exists; the only codon-426 substitution is the query itself, classified uncertain or likely benign.
cspec clinvar generic_acmg_combination_rules PMID:25741868 PMID:16134147 PMID:16557584 PMID:14579148
PS2 Not assessed Not assessed: no proband or parental/trio testing is available, so a confirmed de novo occurrence of this MUTYH variant cannot be established.
cspec PMID:16134147 PMID:25741868
PS3 Not met Not met: the calibrated E. coli BER complementation assay classified p.Arg426Cys with functionally retained variants, below its 1.7-fold retained cutoff.
PMID:25820570 PMID:25741868 cspec clinvar
PS4 Not met Not met: the only occurrence of this allele is one monoallelic carrier among 60 polyposis patients, with no significant case-control enrichment or odds ratio.
cspec clinvar PMID:16134147 PMID:16557584 PMID:14579148 PMID:25741868
PM1 Not met Not met: MUTYH R426 is not a cancer hotspot and this residue carries benign variation (gnomAD 0.083%, 1 homozygote; 11 likely-benign submissions).
cspec clinvar gnomad_v2 generic_acmg_combination_rules PMID:25741868 PMID:25820570 PMID:16134147
PM2 Not met Not met: gnomAD v2.1 AF 0.000831523 and v4.1 AF 0.0013085 both exceed the PM2 supporting rarity threshold of <=0.0001.
gnomad_v2 gnomad_v4 gnomad_canada cspec PMID:25741868 PMID:16134147
PM3 Not met Not met: every primary report places the variant monoallelic (Aceto 2005 GD108, [c.1234C>T]+[c.=]), with no phase-confirmed in-trans pathogenic MUTYH variant.
clinvar PMID:16134147 PMID:16557584 PMID:25741868 gnomad_v2 gnomad_v4
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.1276C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg426Cys). 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 met Not met: no pathogenic missense at MUTYH residue 426 other than the query variant itself was identified in ClinVar or the literature.
cspec clinvar pm5_candidates generic_acmg_combination_rules PMID:25741868 PMID:16134147 PMID:16557584 PMID:14579148
PM6 Not assessed Not assessed: no de novo occurrence of this MUTYH variant is documented in any patient, so assumed de novo status cannot be evaluated.
cspec PMID:16134147 PMID:25741868
PP1 Not assessed Not assessed: no pedigree with genotyped affected relatives exists, so co-segregation of this variant with MUTYH-associated polyposis cannot be demonstrated.
cspec PMID:16134147 PMID:16557584 PMID:25741868
PP2 Not met Not met: MUTYH carries established common benign missense polymorphisms, so the low-benign-missense-rate precondition fails despite missense being a disease mechanism.
cspec clinvar gnomad_v2 generic_acmg_combination_rules PMID:25741868 PMID:16557584 PMID:16134147 PMID:25820570
PP3 Not met Not met: REVEL 0.615 falls below the 0.644 PP3 supporting threshold for this missense variant.
revel bayesdel cspec
PP4 Not met Not met: the single reported carrier had classical FAP (>100 polyps) with vertical transmission, a phenotype atypical for recessive MUTYH-associated polyposis, where 70/71 biallelic patients were attenuated.
cspec PMID:16134147 PMID:16557584 PMID:25741868
PP5 Not met Not met: ClinVar VCV000041753 has zero expert-panel submissions and only a 1-star, conflicting, laboratory-level review status, not an expert-panel pathogenic call.
clinvar cspec
BA1 Not met Not met: the highest observed frequency (gnomAD v4.1 grpmax FAF 0.00160542) sits about 30-fold below the 0.05 BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 cspec PMID:25741868
BS1 Not met Not met: the highest observed frequency (gnomAD v4.1 grpmax FAF 0.00160542) is roughly 6-fold below the generic BS1 strong threshold of 0.01.
gnomad_v2 gnomad_v4 cspec
BS2 Not met Not met: only one gnomAD homozygote is reported and MAP's incomplete, adult-onset penetrance fails the healthy-adult full-penetrance precondition.
gnomad_v2 gnomad_v4 cspec PMID:25741868 PMID:16557584
BS3 Met Met at supporting strength: the controlled E. coli BER complementation assay placed p.Arg426Cys among functionally retained variants, below its 1.7-fold retained cutoff.
PMID:25820570 PMID:25741868 cspec
BS4 Not assessed Not assessed: no genotyped family with multiple affected members exists, so lack of co-segregation of this variant with disease cannot be demonstrated.
cspec PMID:16134147 PMID:16557584 PMID:25741868
BP1 N/A Not applicable: MUTYH disease is driven by biallelic missense alleles such as p.Tyr179Cys and p.Gly396Asp, so the truncating-predominant premise fails.
cspec generic_acmg_combination_rules PMID:25741868 PMID:16557584 PMID:25820570
BP2 Not met Not met: no report places c.1276C>T in cis with a pathogenic MUTYH variant, and the trans clause applies only to dominant disorders.
clinvar PMID:16134147 PMID:16557584 PMID:25741868
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.1276C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg426Cys). 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 0.615 sits far above the 0.29 BP4 supporting threshold for this missense variant.
revel bayesdel cspec
BP5 Not met Not met: the only case carrying this variant was APC-mutation-negative, so no alternate molecular basis for disease was documented.
cspec PMID:16134147 PMID:25741868
BP6 Not met Not met: ClinVar VCV000041753 has zero expert-panel submissions, so no expert-panel benign or likely benign classification exists for this allele.
clinvar cspec
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.1276C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Arg426Cys). 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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