LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-22
Case ID: NM_001128425.2_c.53C_T_20260922_212430
Framework: ACMG/AMP 2015
Variant classification summary

NM_001128425.2:c.53C>T

MUTYH  · NP_001121897.1:p.(Pro18Leu)  · NM_001128425.2
GRCh37: chr1:45800167 G>A  ·  GRCh38: chr1:45334495 G>A
Gene: MUTYH Transcript: NM_001128425.2
Final call
Likely Benign
BS1 strong BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MUTYH
Transcript
NM_001128425.2
Protein
NP_001121897.1:p.(Pro18Leu)
gnomAD AF
0.0004411197999596053 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 (strong) - the variant reaches 1.30% allele frequency in gnomAD v2.1 East Asian samples, above the 1% strong-benign threshold.
2
Likely Benign: BP4 (supporting) - the missense REVEL score of 0.2 indicates a benign protein-level computational effect.
Final determination: Under the generic ACMG/AMP 2015 rules (no usable VCEP or local gene framework being available), one strong benign criterion (BS1) plus one supporting benign criterion (BP4) yields Likely Benign.
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.53C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Pro18Leu). 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 variant carrying the same p.Pro18Leu change exists, and the only c.53C>T records are Benign/Likely benign in ClinVar.
clinvar PMID:18422726 PMID:18811933 PMID:16929514
PS2 Not assessed Not assessed: no source provides parental genotypes or a confirmed de novo occurrence for MUTYH p.Pro18Leu.
cspec clinvar PMID:25741868 PMID:24033266 PMID:18422726 PMID:18811933 PMID:16929514
PS3 Not met Not met: the validated 47-variant MUTYH complementation assay scored p.Pro18Leu as a 2.7-fold partial defect, an intermediate result that is not a well-established damaging effect.
cspec PMID:18811933 PMID:18422726 PMID:25741868 PMID:16929514
PS4 Not met Not met: the p.Pro18Leu enrichment (OR 4.43, CI 1.33-14.72) is haplotype-level and gastric-cancer-only, with no case-control excess in MUTYH-associated polyposis.
PMID:16929514 PMID:18811933 PMID:18422726 PMID:25741868 cspec
PM1 Not met Not met: no approved MUTYH critical-domain entry covers residue 18, and the region carries benign variation reaching 1.3% in East Asian gnomAD v2.1.
cspec gnomad_v2 clinvar PMID:16929514
PM2 Not met Not met: the gnomAD v4.1 all-comers frequency of 0.0441% is above the generic PM2 threshold of 0.01%.
cspec gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not met Not met: the one reported affected proband carries c.53C>T alongside G25D, Q324H and c.1389G>C, none of which is an established pathogenic trans partner.
cspec PMID:18422726 PMID:16929514 PMID:18811933 PMID:21325953 PMID:25741868
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.53C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Pro18Leu). 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 alternate missense at MUTYH Pro18 is established pathogenic; the system-wide ClinVar screen returned zero same-residue comparators.
clinvar pm5_candidates PMID:18422726 PMID:18811933 PMID:16929514
PM6 Not assessed Not assessed: no parental testing or presumed de novo evidence is documented for MUTYH p.Pro18Leu.
cspec clinvar PMID:25741868 PMID:24033266 PMID:18422726 PMID:18811933 PMID:16929514
PP1 Not assessed Not assessed: no relative genotypes or informative meioses are reported for MUTYH p.Pro18Leu.
cspec clinvar PMID:24033266 PMID:18422726 PMID:18811933 PMID:16929514 PMID:21325953
PP2 Not met Not met: MUTYH lacks missense constraint (gnomAD mis_z 0.63) and carries common benign missense alleles, so the low-benign-missense-rate arm of PP2 fails.
cspec gnomad_v4 gnomad_v2 PMID:18422726 PMID:21325953
PP3 Not met Not met: this missense variant's REVEL score of 0.2 is below the >=0.644 PP3 supporting threshold.
revel cspec
PP4 Not met Not met: no MUTYH-specific phenotype is documented - adenomatous polyposis overlaps APC-associated FAP and Lynch syndrome, and no proband phenotype accompanies this variant.
PMID:18422726 PMID:21325953 PMID:25741868 cspec
PP5 Not met Not met: the ClinVar record (20 submissions, 0 expert-panel) has no expert-panel assertion, and its conflicting 1-star lab classifications cannot support PP5.
clinvar cspec
BA1 Not met Not met: the highest credible frequency is 1.30% (gnomAD v2.1 East Asian), below the generic BA1 stand-alone threshold of 5%.
cspec gnomad_v2 gnomad_v4 PMID:25741868
BS1 Met Met at strong: gnomAD v2.1 East Asian frequency 1.30% exceeds the generic BS1 threshold of 1%.
cspec gnomad_v2 gnomad_v4 PMID:18811933 PMID:16929514
BS2 Not assessed Not assessed: 4-7 gnomAD homozygotes are reported, but healthy-adult status, age and phenotype are undocumented for this adult-onset recessive disorder.
cspec gnomad_v2 gnomad_v4 PMID:25741868 PMID:21325953
BS3 Not met Not met: the validated MUTYH complementation assay shows a 2.7-fold partial defect rather than normal function, and the mitochondrial-localization result is an unvalidated one-component proxy.
cspec PMID:18811933 PMID:25741868 PMID:18422726 spliceai
BS4 Not assessed Not assessed: no genotyped affected relatives or documented non-segregation exist for MUTYH p.Pro18Leu.
cspec clinvar PMID:18422726 PMID:18811933 PMID:16929514 PMID:21325953
BP1 Not met Not met: MUTYH disease is caused by biallelic missense alleles (biallelic p.Gly272Glu/p.Ala359Val reported in an affected patient), not primarily truncating variants.
cspec PMID:18422726 PMID:21325953 pvs1_gene_context
BP2 Not met Not met: the only documented cis partner, c.74G>A (p.Gly25Asp), is not an established pathogenic MUTYH variant.
cspec PMID:16929514 PMID:18811933 PMID:18422726 PMID:21325953 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.53C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Pro18Leu). 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 Met Met (supporting): missense REVEL score 0.2 is at or below the <=0.29 BP4 supporting threshold.
revel cspec clinvar
BP5 Not met Not met: the only polyposis patient documented with this variant was APC-negative and classed as MAP, so no alternate molecular basis is documented.
PMID:18422726 PMID:16929514 PMID:18811933 PMID:25741868 cspec
BP6 Not met Not met: ClinVar's Benign content is entirely from 20 ordinary laboratory submissions with 0 expert-panel assertions and a 1-star conflicting status.
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.53C>T in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Pro18Leu). 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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