Variant classification summary

NM_001128425.2:c.1187G>A

MUTYH · NP_001121897.1:p.(Gly396Asp) · NM_001128425.2

GRCh37: chr1:45797228 C>T · GRCh38: chr1:45331556 C>T

Gene: MUTYH Transcript: NM_001128425.2

Final call

Likely Pathogenic

PS3 moderate PM1 supporting PP3 strong

Variant details

Gene

MUTYH

Transcript

NM_001128425.2

Protein

NP_001121897.1:p.(Gly396Asp)

gnomAD AF

0.004730045392078258 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 moderate—p.G396D caused a 1.7-fold higher mutation rate than wild-type MUTYH and was partially defective.

2

Likely Pathogenic: PM1 supporting—residue 396 lies in MUTYH's functionally critical C-terminal 8-oxo-guanine recognition domain.

3

Likely Pathogenic: PP3 strong—REVEL 0.954 exceeds the strong threshold of 0.932.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion (PP3), one moderate pathogenic criterion (PS3), and one supporting pathogenic criterion (PM1) support a Likely Pathogenic classification.

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.1187G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly396Asp). 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 assessed	Not assessed: no distinct pathogenic nucleotide change producing p.Gly396Asp was documented in the reviewed evidence.	PMID:19506731 PMID:25820570
PS2	Not assessed	Not assessed: no documented proband-parent genotypes or confirmed de novo status are available for c.1187G>A.	cspec
PS3	Met	Met, moderate: p.G396D caused a 1.7-fold higher mutation rate than wild-type MUTYH and was classified as partially defective in a controlled complementation assay.	cspec PMID:25820570 PMID:19506731
PS4	Not assessed	Not assessed: the available odds ratio 6.87 applies to c.1103G>A, not the assessed c.1187G>A variant, so exact-variant enrichment is unavailable.	clinvar PMID:19506731 PMID:25820570
PM1	Met	Met, supporting: residue 396 lies in the C-terminal 8-oxo-guanine recognition domain described as functionally critical for MUTYH repair.	cspec PMID:19506731 PMID:25820570
PM2	Not met	Not met: the non-cancer exome allele frequency is 0.00295109, exceeding the PM2 threshold of 0.0001.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: PMID:19506731 describes biallelic G396D cell lines but documents no affected proband, pathogenic allele in trans, or phase.	cspec PMID:19506731
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.1187G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly396Asp). 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 assessed	Not assessed: no distinct pathogenic missense substitution at residue 396 was documented, and the comparator search returned zero candidates.	cspec
PM6	Not assessed	Not assessed: no plausible unconfirmed de novo occurrence of c.1187G>A is reported in the available evidence.	cspec
PP1	Not assessed	Not assessed: no informative relatives, genotypes, phenotypes, or meioses are reported for segregation of c.1187G>A.	cspec
PP2	Not assessed	Not assessed: no validated MUTYH gene-level missense-enrichment or low-benign-missense metric was available for PP2.	cspec
PP3	Met	Met, strong: missense REVEL score 0.954 exceeds the >=0.932 strong PP3 threshold.	cspec revel
PP4	Not assessed	Not assessed: p.G396D is associated with MUTYH-associated polyposis, but the patient's specific phenotype and family history are not available.	PMID:19506731 PMID:25820570
PP5	Not met	Not met: ClinVar shows zero expert-panel submissions, and the displayed record maps to c.1103G>A rather than the assessed c.1187G>A.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 0.00588456, below the generic BA1 threshold of 0.05.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed allele frequency is 0.00588456, below the generic BS1 threshold of 0.01.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 26 homozygotes, but unaffected status, age, and disease ascertainment are unavailable for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: p.G396D caused a 1.7-fold higher mutation rate than wild-type MUTYH and was classified as partially defective, not functionally normal.	PMID:25820570 PMID:19506731
BS4	Not assessed	Not assessed: no tested unaffected relatives or family genotype-phenotype data demonstrate non-segregation of c.1187G>A.	cspec
BP1	Not assessed	Not assessed: no validated gene-level evidence showed that MUTYH disease is predominantly caused by truncating rather than missense variants.	cspec
BP2	Not assessed	Not assessed: no second pathogenic MUTYH variant or cis-phase observation is documented for the autosomal-recessive disorder.	cspec
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.1187G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly396Asp). 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	Not met	Not met: missense REVEL score 0.954 exceeds the <=0.29 supporting BP4 threshold.	cspec revel
BP5	Not assessed	Not assessed: no qualifying alternative molecular explanation or applicable MUTYH-specific BP5 rule is documented for this case.	cspec
BP6	Not met	Not met: ClinVar reports zero expert-panel submissions and no exact-variant benign or likely-benign expert-panel assertion.	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.1187G>A in MUTYH is a missense substitution predicted to produce NP_001121897.1:p.(Gly396Asp). 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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