Variant classification summary

NM_001048174.2:c.1103G>A

MUTYH · NP_001041639.1:p.(Gly368Asp) · NM_001048174.2

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

Gene: MUTYH Transcript: NM_001048174.2

Final call

Pathogenic

PS1 strong PS3 supporting PS4 strong PM3 moderate PP1 supporting PP3 strong

Variant details

Gene

MUTYH

Transcript

NM_001048174.2

Protein

NP_001041639.1:p.(Gly368Asp)

gnomAD AF

0.004730045392078258 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong, the identical p.Gly368Asp substitution was previously reported as pathogenic.

2

Pathogenic: PS3 supporting, adenine-removal activity was reduced approximately 85–86% versus wild type.

3

Pathogenic: PS4 strong, affected-case enrichment produced OR 23.38 with confidence interval excluding 1.0.

4

Pathogenic: PM3 moderate, affected siblings carried the variant in trans with another disease-associated MUTYH variant.

5

Pathogenic: PP1 supporting, the variant co-segregated with disease in three affected siblings.

6

Pathogenic: PP3 strong, REVEL 0.954 exceeds the 0.932 strong threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS1 and PS4) satisfy the Pathogenic combination rule; higher- or lower-strength applied pathogenic criteria do not alter that call.

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 identical Gly-to-Asp substitution was reported as pathogenic in biallelic MAP cases under alternate MUTYH numbering.	PMID:11818965 PMID:16557584
PS2	Not assessed	Not assessed: no documented de novo occurrence with confirmed maternity, confirmed paternity, disease in the patient, and no family history is available.
PS3	Met	Met at supporting: adenine-removal activity was reduced approximately 85–86% versus wild type in disease-relevant assays, but the study used a bacterial homolog rather than a validated clinical assay.	PMID:11818965
PS4	Met	Met: 31/658 case chromosomes versus 0/232 control chromosomes gives continuity-corrected OR 23.38 (95% CI 1.42-383.64), exceeding the OR >5.0 threshold with CI excluding 1.0.	PMID:16557584
PM1	Not assessed	Not assessed: residue 368 lacks an authoritative critical-domain or qualifying hotspot designation, and no benign-variation exclusion is documented.	cspec hotspots
PM2	Not met	Not met: gnomAD v4.1 AF is 0.00473005 with 26 homozygotes, exceeding the PM2 threshold of 0.0001.	gnomad_v4 cspec
PM3	Met	Met at moderate strength: three affected siblings were compound heterozygotes for this allele and Tyr165Cys, demonstrating the queried variant in trans.	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 pathogenic missense change different from Gly368Asp is documented at residue 368; the available comparator is the identical substitution.	pm5_candidates PMID:11818965 PMID:16557584
PM6	Not assessed	Not assessed: no assumed de novo occurrence without confirmed maternity and paternity is documented for this variant.
PP1	Met	Met at supporting strength: three affected siblings carried the variant, while unaffected relatives were heterozygous for one allele or negative.	PMID:11818965
PP2	Not assessed	Not assessed: the two required gene-level conditions—low benign missense variation and a common missense disease mechanism—are not established.
PP3	Met	Met strong: missense REVEL 0.954 meets the >=0.932 PP3 threshold.	revel
PP4	Not assessed	Not assessed: the individual patient's phenotype and family history are not provided, so specificity for a single genetic etiology cannot be judged.	PMID:16557584
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel submission; its Pathogenic/Likely pathogenic labels are laboratory assertions and cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00576855, below the generic BA1 threshold of 0.05.	gnomad_v4 cspec
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00576855, below the generic BS1 default threshold of 0.01.	gnomad_v4 cspec
BS2	Not assessed	Not assessed: gnomAD reports 26 homozygotes, but provides no documented healthy-adult phenotype or age information for BS2.	gnomad_v4 cspec
BS3	Not met	Not met: the allele's adenine-removal activity was approximately 85–86% below wild type, providing damaging rather than benign functional evidence.	PMID:11818965
BS4	Not assessed	Not assessed: no affected relative is documented as variant-negative, so lack of segregation cannot be established.	PMID:11818965
BP1	Not assessed	Not assessed: the evidence does not show that MUTYH disease is caused primarily by truncating variants rather than missense variants.
BP2	Not met	Not met: the reported family genotype is trans, not cis, and MUTYH-associated polyposis is autosomal recessive rather than fully penetrant dominant.	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: missense REVEL 0.954 exceeds the strongest BP4 threshold of <=0.016.	revel
BP5	Not assessed	Not assessed: no evidence documents an alternate molecular basis for disease in the case carrying this variant.	PMID:16557584
BP6	Not met	Not met: no exact-variant expert-panel benign or likely benign classification is present, while the available ClinVar assertions are pathogenic laboratory submissions.	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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