LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-07
Case ID: NM_001048174.2_c.452A_G_20261107_031748
Framework: ACMG/AMP 2015
Variant classification summary

NM_001048174.2:c.452A>G

MUTYH  · NP_001041639.1:p.(Tyr151Cys)  · NM_001048174.2
GRCh37: chr1:45798475 T>C  ·  GRCh38: chr1:45332803 T>C
Gene: MUTYH Transcript: NM_001048174.2
Final call
Pathogenic
PS1 strong PS3 strong PM3 moderate PP1 supporting PP3 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
MUTYH
Transcript
NM_001048174.2
Protein
NP_001041639.1:p.(Tyr151Cys)
gnomAD AF
0.0019217140053426375 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 strong—Tyr151Cys was previously reported as Tyr165Cys under historical MUTYH numbering.
2
Pathogenic: PS3 strong—independent functional assays showed markedly reduced or absent MUTYH repair activity.
3
Pathogenic: PM3 moderate—the variant was in trans with Gly382Asp in three affected siblings.
4
Pathogenic: PP1 supporting—the variant segregated with disease in three affected siblings.
5
Pathogenic: PP3 strong—REVEL 0.963 exceeds the 0.932 strong threshold.
Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as Pathogenic when at least two strong pathogenic criteria are satisfied; PS1 and PS3 meet that rule.
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 Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Met Met: the exact Tyr151Cys substitution was previously reported as Tyr165Cys (494A>G) in affected siblings and functional testing.
PMID:11818965
PS2 Not assessed Not assessed: no confirmed maternity-and-paternity testing demonstrates that c.452A>G arose de novo in the proband.
PS3 Met Met, strong: independent enzymatic, bacterial-complementation, and mammalian-cell assays consistently showed markedly reduced or absent MUTYH repair activity for Y151C/Y165C.
PMID:11818965 PMID:19836313 PMID:19953527
PS4 Not assessed Not assessed: reported OR ≈50:1 satisfies 50 > 5.0, but no 95% confidence interval is provided to confirm that it excludes 1.0.
PMID:11818965
PM1 Not assessed Not assessed: Y151 has no recorded significant hotspot, while no complete critical-domain and benign-variation assessment is available.
cspec hotspots
PM2 Not met Not met: gnomAD v4.1 AF is 0.001921714, exceeding the 0.0001 PM2 supporting threshold, with the variant observed in 3,102 alleles.
gnomad_v2 gnomad_v4
PM3 Met Met: c.452A>G was in trans with Gly382Asp in three affected siblings with multiple colorectal adenomas and carcinoma, establishing recessive biallelic disease-phase evidence.
PMID:11818965
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no confirmed different pathogenic missense change at Tyr151 was identified, but completeness of the residue-level comparator search is unresolved.
pm5_candidates PMID:11818965
PM6 Not assessed Not assessed: the available report shows familial segregation, not an assumed de novo variant without parental confirmation.
PP1 Met Met at supporting: the variant occurred in trans with Gly382Asp in three affected siblings, while unaffected relatives carried one variant or neither.
PMID:11818965
PP2 Not assessed Not assessed: available studies show pathogenic MUTYH missense variants but provide no gene-level benign-missense rate or mechanism-frequency evidence.
PMID:19836313 PMID:19953527 gnomad_v4
PP3 Met Met, strong: REVEL 0.963 exceeds the strong PP3 threshold of 0.932 for this missense variant.
revel generic_acmg_combination_rules
PP4 Not met Not met: multiple colorectal adenomas and carcinoma are compatible with MUTYH-associated polyposis but are not specific to a single genetic etiology.
PMID:11818965
PP5 Not met Not met: ClinVar reports Pathogenic/Likely pathogenic, but the exact variant has zero expert-panel submissions.
clinvar
BA1 Not met Not met: gnomAD grpmax FAF is 0.00236984, below the 0.05 BA1 threshold, and the pathogenic ClinVar consensus makes a stand-alone benign call inappropriate.
gnomad_v2 gnomad_v4 clinvar
BS1 Not met Not met: the highest applicable grpmax FAF is 0.00236984, below the 0.01 BS1 default, with no validated maximum-credible-frequency calculation supporting a higher threshold.
gnomad_v2 gnomad_v4 clinvar
BS2 Not assessed Not assessed: gnomAD reports 5 homozygotes, but provides no individual age or phenotype data proving they were healthy adults with expected early penetrance.
gnomad_v4
BS3 Not met Not met: variant-specific assays showed absent or markedly reduced MUTYH glycosylase and oxidative-DNA repair activity rather than preserved function.
PMID:11818965 PMID:19836313 PMID:19953527
BS4 Not met Not met: three affected siblings carried the variant in trans with Gly382Asp, and unaffected relatives carried one variant or neither.
PMID:11818965
BP1 Not assessed Not assessed: MUTYH disease literature includes missense alleles, but no comparative evidence shows that truncating variants primarily cause disease.
PMID:19836313 PMID:19953527 PMID:16557584
BP2 Not met Not met: the only reported configuration was trans in an autosomal recessive disorder, whereas BP2 requires cis evidence or trans evidence in a fully penetrant dominant disorder.
PMID:11818965
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.963 is above the BP4 supporting cutoff of 0.29 for this missense variant.
revel generic_acmg_combination_rules
BP5 Not met Not met: no reviewed case links this variant to disease with an established alternate molecular basis.
PMID:11818965
BP6 Not met Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification; its available aggregate classification is pathogenic.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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