LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-22
Case ID: NM_001128425.2_c.74G_A_20260922_194235
Framework: ACMG/AMP 2015
Variant classification summary

NM_001128425.2:c.74G>A

MUTYH  · NP_001121897.1:p.(Gly25Asp)  · NM_001128425.2
GRCh37: chr1:45800146 C>T  ·  GRCh38: chr1:45334474 C>T
Gene: MUTYH Transcript: NM_001128425.2
Final call
Likely Benign
BS1 strong BS3 supporting 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.(Gly25Asp)
gnomAD AF
0.0004411055890308439 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 strong because the East Asian allele frequency exceeds 1%.
2
Likely Benign: BS3 supporting because p.Gly25Asp was functionally retained in controlled complementation testing.
3
Likely Benign: BP4 supporting because REVEL 0.111 is below the benign computational threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion plus at least one supporting benign criterion supports Likely Benign; this case has BS1 strong, BS3 supporting, and BP4 supporting.
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.74G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly25Asp). 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: MUTYH p.Gly25Asp is reported, but no reliable pathogenic classification establishes the same amino-acid change as a PS1 comparator.
clinvar PMID:18422726 PMID:17703316 PMID:18811933 PMID:25820570
PS2 Not assessed Not assessed: no proband-parent genotypes or confirmed de novo occurrence are documented for p.Gly25Asp.
cspec PMID:18422726 PMID:17703316
PS3 Not met Not met: p.G25D was functionally retained in complementation testing, with a mutation rate below the study's 1.7-fold defect threshold relative to wild type.
PMID:25820570 PMID:18811933
PS4 Not met Not met: the reported 6/138 versus 3/343 enrichment concerned a linked c.53C>T/c.74G>A haplotype, not isolated c.74G>A.
PMID:18811933 PMID:17703316 PMID:18422726
PM1 Not met Not met: residue 25 is not supported by an approved MUTYH critical-domain entry or a statistically significant hotspot in the available specification materials.
cspec
PM2 Not met Not met: the gnomAD v4.1 all-comers frequency is 0.000441106, above the PM2 threshold of 0.0001.
cspec gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: one affected patient had four heterozygous MUTYH variants, but the pathogenic partner and phase relative to p.G25D were not established.
cspec PMID:18422726 PMID:17703316 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.74G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly25Asp). 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 variant at MUTYH Gly25 has an established pathogenic classification, and zero same-residue candidates were identified.
clinvar PMID:18422726 PMID:17703316 PMID:18811933
PM6 Not assessed Not assessed: no parental testing or presumed de novo evidence is documented for p.Gly25Asp.
cspec PMID:18422726 PMID:17703316
PP1 Not assessed Not assessed: no affected-relative genotypes, unaffected-relative testing, or informative meioses are reported for p.Gly25Asp.
cspec PMID:18422726 PMID:17703316 PMID:25820570
PP2 Not met Not met: MUTYH has an established loss-of-function mechanism and documented missense variation, without evidence that pathogenic variants are predominantly missense.
cspec PMID:25820570 PMID:18422726
PP3 Not met Not met: REVEL 0.111 is below the >=0.644 PP3 supporting threshold for this missense variant.
cspec revel
PP4 Not met Not met: reported adenomatous polyposis and colorectal cancer are not sufficiently specific because the linked p.P18L-p.G25D combination also occurred in three controls.
PMID:17703316 PMID:18422726 PMID:18811933
PP5 Not met Not met: ClinVar lists zero expert-panel submissions for this exact variant, and the available assertions are non-expert laboratory classifications.
clinvar
BA1 Not met Not met: the highest observed frequency is 1.30313%, below the generic BA1 stand-alone threshold of 5%.
cspec gnomad_v2 gnomad_v4 PMID:25741868
BS1 Met Met at strong: the East Asian gnomAD v2.1 frequency is 1.30313%, exceeding the generic BS1 threshold of 1%.
cspec gnomad_v2 gnomad_v4 PMID:17703316 PMID:18811933
BS2 Not assessed Not assessed: gnomAD shows 4–7 homozygotes, but their health status, age, and MUTYH disease phenotypes are not established.
cspec gnomad_v2 gnomad_v4 PMID:25741868
BS3 Met Met at supporting: p.G25D was functionally retained in a controlled BER complementation assay below the 1.7-fold defect threshold relative to wild type.
PMID:25820570 PMID:18811933
BS4 Not assessed Not assessed: no adequately tested affected family members or documented non-segregation are available for p.Gly25Asp.
cspec PMID:18422726 PMID:17703316
BP1 Not met Not met: MUTYH has a loss-of-function mechanism, but substantial missense variation and missense functional testing prevent calling missense variants generally benign.
cspec PMID:25820570 PMID:18422726 PMID:18811933
BP2 Not assessed Not assessed: p.G25D was in cis with p.P18L, but p.P18L was not established as pathogenic or likely pathogenic for the recessive disorder.
cspec PMID:17703316 PMID:18422726 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.74G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly25Asp). 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: REVEL 0.111 is below the <=0.29 BP4 supporting threshold for this missense variant.
cspec revel
BP5 Not assessed Not assessed: additional MUTYH variants were reported, but none was established as a convincing alternative pathogenic explanation for the patient's phenotype.
PMID:17703316 PMID:18422726
BP6 Not met Not met: ClinVar lists zero expert-panel submissions for this exact variant, despite several ordinary laboratory Benign or Likely benign assertions.
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.74G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly25Asp). 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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