LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-11
Case ID: NM_001128425.2_c.1465G_A_20260811_154747
Framework: ACMG/AMP 2015
Variant classification summary

NM_001128425.2:c.1465G>A

MUTYH  · NP_001121897.1:p.(Ala489Thr)  · NM_001128425.2
GRCh37: chr1:45796865 C>T  ·  GRCh38: chr1:45331193 C>T
Gene: MUTYH Transcript: NM_001128425.2
Final call
VUS
PS3 moderate PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MUTYH
Transcript
NM_001128425.2
Protein
NP_001121897.1:p.(Ala489Thr)
gnomAD AF
3.965210236685877e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 (Moderate): E. coli complementation assay showed a 3.2-fold increased mutation rate, a partial functional defect comparable to founder-pathogenic p.G396D (1.7-fold).
2
PM2 (Supporting): allele frequency 0.004% in gnomAD (0 homozygotes), about 25-fold below the 0.1% threshold for recessive disorders.
3
PP3 (Supporting): REVEL 0.724 predicts a deleterious missense effect (SVI supporting band 0.644-0.772).
4
Combination: one moderate plus two supporting criteria meets no pathogenic or benign threshold under ACMG/AMP 2015; final classification VUS.
Final determination: Generic ACMG/AMP 2015 fallback combination rules apply because the InSiGHT MUTYH VCEP v1.0 framework was unusable (empty rule payload); the applied combination (1 moderate PS3 + 2 supporting PM2/PP3) meets no Pathogenic or Likely Pathogenic threshold and no Benign or Likely Benign threshold, 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 Not applicable: c.1465G>A is a missense change (p.Ala489Thr), so no null-variant mechanism such as nonsense-mediated decay is triggered.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: p.Ala489Thr is not established as pathogenic - ClinVar VCV000142138 is Uncertain significance across all 15 submitters.
clinvar PMID:25820570 PMID:20618354 PMID:15761860 PMID:16234049 PMID:25741868
PS2 N/A Not applicable: no de novo observation or parental testing exists, and MUTYH-associated polyposis is recessive, so a single de novo allele cannot establish pathogenicity.
PMID:25741868 cspec PMID:20618354 PMID:25820570 clinvar
PS3 Met Met (moderate): E. coli complementation assay showed a 3.2-fold increased mutation rate, a partial defect comparable to founder-pathogenic p.G396D (1.7-fold).
PMID:25820570 PMID:25741868 cspec clinvar
PS4 Not assessed Not assessed: no case-control or cohort-enrichment study of this exact variant exists - only a single monoallelic case report without controls.
PMID:20618354 PMID:15761860 PMID:16234049 PMID:25820570 clinvar
PM1 Not met Not met: residue 489 lies outside any confirmed mutational hotspot or defined critical functional domain.
PMID:25820570 PMID:15761860 PMID:16234049 oncokb PMID:25741868
PM2 Met Met (supporting): gnomAD allele frequency 0.004% (0 homozygotes), about 25-fold below the 0.1% threshold for recessive disorders.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not met Not met: trans configuration with a pathogenic allele is unconfirmed - the only co-occurrence report states phase was unknown.
PMID:20618354 PMID:25820570 PMID:15761860 PMID:16234049 PMID:25741868 clinvar
PM4 N/A Not applicable: missense change causes no protein length alteration, so the in-frame insertion/deletion criterion does not apply.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no pathogenic alternate missense at codon 489 was identified, and no complete variant inventory was available to exclude one.
pm5_candidates clinvar PMID:25820570 PMID:20618354 PMID:15761860 PMID:16234049 PMID:25741868
PM6 N/A Not applicable: no assumed de novo occurrence is reported, and in this recessive disorder a single de novo allele cannot establish pathogenicity.
PMID:25741868 cspec PMID:20618354 PMID:25820570 clinvar
PP1 Not assessed Not assessed: no co-segregation data exist - affected relatives of the single reported carrier were not tested.
PMID:20618354 PMID:25820570 clinvar PMID:25741868 cspec
PP2 Not assessed Not assessed: missense is a common MUTYH disease mechanism, but gene-level missense constraint data were unavailable to confirm a low benign-missense rate.
PMID:25820570 PMID:16234049 PMID:15761860 PMID:25741868
PP3 Met Met (supporting): REVEL 0.724 falls in the supporting band (0.644-0.772) for a predicted deleterious missense effect.
revel spliceai bayesdel cspec PMID:25741868
PP4 Not met Not met: the only observation is a single heterozygous carrier, which does not establish the biallelic phenotype of this recessive disorder.
PMID:20618354
PP5 Not met Not met: no ClinVar expert panel has classified this variant - all 15 submissions are from clinical laboratories.
clinvar
BA1 Not met Not met: gnomAD allele frequency 0.004% is far below the >1% stand-alone benign threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: gnomAD allele frequency 0.004% is far below the >0.3% threshold and below MUTYH founder carrier frequencies.
gnomad_v2 gnomad_v4 PMID:25741868
BS2 Not met Not met: no healthy homozygous individuals observed - 0 homozygotes in gnomAD v2.1 and v4.1.
gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS3 Not met Not met: the only functional data show a damaging effect (3.2-fold increased mutation rate), directly contradicting a no-effect conclusion.
PMID:25820570 PMID:25741868 oncokb
BS4 Not assessed Not assessed: no affected family members have been genotyped, so lack of segregation cannot be tested.
PMID:20618354 PMID:25820570 clinvar PMID:25741868 cspec
BP1 Not met Not met: MUTYH-associated polyposis is caused predominantly by missense variants, so the truncating-disease premise does not apply.
PMID:25820570 PMID:16234049 PMID:15761860 PMID:25741868
BP2 Not met Not met: no cis configuration with a pathogenic variant is reported - the only co-occurrence report states phase was unknown.
PMID:20618354 PMID:25820570 PMID:15761860 PMID:16234049 PMID:25741868 clinvar
BP3 N/A Not applicable: missense change does not alter protein length in a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: the calibrated in-silico evidence (REVEL 0.724) predicts a deleterious effect, directly contradicting BP4.
spliceai revel bayesdel cspec PMID:25741868
BP5 Not assessed Not assessed: no alternate molecular cause (e.g., APC or MMR variants) is documented in any carrier of this variant.
BP6 Not met Not met: no ClinVar expert panel has classified this variant as Benign or Likely benign.
clinvar
BP7 N/A Not applicable: this is a missense change, not a synonymous variant, so the silent-variant criterion does not apply.
generic_acmg_combination_rules
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