Classification rationale

PVS1PM2 Likely Pathogenic

MUTYH c.309G>A nonsense · exon 3

Likely Pathogenic: PVS1 (very strong) supports a loss-of-function effect from the early p.Trp103Ter truncation. Likely Pathogenic: PM2 (supporting) is met because the maximum gnomAD population frequency is below 0.0001.

PVS1 + PM2 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001128425.2 · variants mapped to exon structure

MUTYH NM_001128425.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met at very strong: nonsense p.Trp103Ter truncates the 550-amino-acid MUTYH protein at residue 103, with no evidence of a downgrade-triggering NMD escape or distal non-critical region.

The governing MUTYH framework names NM_001128425.2 as the preferred transcript and provides no gene-specific PVS1 rule payload or downgrade decision tree.The normalized consequence is nonsense: NM_001128425.2:c.309G>A causes NP_001121897.1:p.(Trp103Ter), with the predicted product ending at residue 103 while the reference protein ends at residue 550.The generic ClinGen SVI PVS1 framework supports full-strength assessment of a nonsense variant when loss of function is an established disease mechanism, with downgrades considered for NMD escape, non-critical distal regions, irrelevant exons/transcripts, or population-enriched loss-of-function regions.

cspec ↗pvs1_generic_framework ↗

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v4.1 maximum population AF 3.8134e-05 is below the 0.0001 PM2 threshold.

The InSiGHT MUTYH Version 1.0 framework was checked first; its retrieved rule payload contains no population-specific PM2 threshold or population-source override, so the default all-comers datasets were used.gnomAD v4.1 reports overall AF 2.7879279004672568e-05 from 45/1614102 alleles, maximum named-subpopulation AF 3.813404200507098e-05 in European (non-Finnish) individuals, and 0 homozygotes.gnomAD v2.1 reports AF 3.9763328667769435e-06 from 1/251488 alleles and 0 homozygotes; the highest named-subpopulation AF is 8.790126929432861e-06.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no documented parental genotypes or confirmed de novo occurrence is available for the affected proband.

PS3 Not assessed: no validated functional assay directly tested MUTYH c.309G>A (p.Trp103Ter), so PS3 strength cannot be calibrated from the available evidence.

PS4 Not assessed: the available 302-person cohort report lacks exact-variant case counts, controls, enrichment, odds ratio, or statistical significance for NM_001128425.2:c.309G>A.

PM3 Not assessed: no affected-proband genotype, second pathogenic MUTYH allele, or phase information is documented to evaluate biallelic inheritance.

PM6 Not assessed: no apparently de novo proband observation or parental-testing context is reported for this variant.

PP1 Not assessed: no informative relatives, segregating meioses, or genotype–phenotype co-segregation data are reported.

PP4 Not assessed: no patient phenotype or phenotype-specific clinical features are provided to establish a match with MUTYH-associated polyposis.

PP5 Not met: ClinVar has 12 Pathogenic and one Likely pathogenic laboratory assertions, but zero exact-variant expert-panel submissions.

Benign

BA1 Not met: gnomAD v4.1 maximum population AF 3.8134e-05 is far below the 0.05 BA1 threshold.

BS1 Not met: gnomAD v4.1 maximum population AF 3.8134e-05 is below the generic 0.01 BS1 threshold.

BS2 Not met: gnomAD reports 0 homozygotes, so no unaffected-homozygote observation supports BS2.

BS3 Not assessed: no validated benign functional assay directly tested MUTYH c.309G>A (p.Trp103Ter) or demonstrated preserved function.

BS4 Not assessed: no unaffected carrier with adequate phenotype and age information is documented to demonstrate non-segregation.

BP2 Not assessed: no same-individual co-occurrence with a pathogenic variant and no cis/trans phase information are documented for BP2.

BP5 Not assessed: no alternate pathogenic cause, second disease-causing variant, or relevant co-occurrence evidence is documented.

BP6 Not met: the exact-match ClinVar audit reports zero expert-panel submissions and no Benign or Likely benign expert-panel classification.

N/A · 10 PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.78793e-05; MAF= 0.00279%, 45/1614102 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.8134e-05; MAF= 0.00381%, 45/1180048 alleles, homozygotes = 0); grpmax FAF= 2.907e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97633e-06; MAF= 0.00040%, 1/251488 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79013e-06; MAF= 0.00088%, 1/113764 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0028% · 45 / 1,614,102
0 hom · FAF 0.0029%

European (non-Finnish)

45 / 1,180,048

0.0038%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,488
0 hom

European (non-Finnish)

1 / 113,764

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (12 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 184976)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). BayesDel score = 0.655873.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

PMID 25741868 ↗ CLINVAR · functional

Found

).

Applied to

→PM2 supporting

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

21962078 ↗ Breakpoint characterization of a novel large intragenic deletion of MUTYH detected in a MAP patient: case report. ONCOKB

23108399 ↗ Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. ONCOKB

18534194 ↗ Characterization of mutant MUTYH proteins associated with familial colorectal cancer. CLINVAR

25525159 ↗ RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

15761860 ↗ Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations. CLINVAR

20663686 ↗ MUTYH-associated polyposis (MAP). CLINVAR

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