NM_005359.6:c.1082G>A

SMAD4 · NP_005350.1:p.(Arg361His) · NM_005359.6

GRCh37: chr18:48591919 G>A · GRCh38: chr18:51065549 G>A

Gene: SMAD4 Transcript: NM_005359.6

Final call

Pathogenic

PS3 strong PM2 supporting PP3 strong

Variant details

Gene

SMAD4

Transcript

NM_005359.6

Protein

NP_005350.1:p.(Arg361His)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Pathogenic: PS3 strong is supported by two assays showing disrupted or abolished Smad2-Smad4 complex formation.

Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

Pathogenic: PP3 strong is met because REVEL 0.955 exceeds the strong threshold of 0.932.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria satisfy the Pathogenic combination rule; PS3 strong and PP3 strong meet that requirement, with PM2 supporting additional evidence.

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	Not assessed	Not assessed: no previously established pathogenic Arg361His caused by a different nucleotide change was documented for codon 361.	clinvar PMID:11274206 PMID:11779503 spliceai
PS2	Not assessed	Not assessed: no documented maternity-and-paternity confirmation or case-specific de novo result is available for SMAD4 c.1082G>A.
PS3	Met	Met, strong: two variant-specific recombinant-protein assays consistently found that SMAD4 R361H disrupted or completely abolished Smad2-Smad4 complex formation.	PMID:11274206 PMID:11779503
PS4	Not assessed	Not assessed: affected-case reports lack control counts or an odds ratio and 95% confidence interval required to show OR >5.0 with a CI excluding 1.0.	PMID:11274206 PMID:15014009 PMID:11779503
PM1	Not assessed	Not assessed: Arg361 is within the reported MH2 mutational cluster (330-370), but absence of benign variation in that region was not established.	cspec PMID:15014009 PMID:11779503
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, corresponding to frequency 0, below the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: SMAD4-related juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome is documented as autosomal dominant, while PM3 is restricted to recessive disorders.	cspec
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 established pathogenic missense substitution different from Arg361His was documented at residue 361.	clinvar PMID:11274206 PMID:11779503 PMID:15014009
PM6	Not assessed	Not assessed: no case-specific evidence shows an assumed de novo SMAD4 c.1082G>A result without parental confirmation.
PP1	Not assessed	Not assessed: no affected-family-member genotypes or meioses demonstrate co-segregation of SMAD4 c.1082G>A with disease.
PP2	Not assessed	Not assessed: SMAD4 loss of function is supported, but no qualifying low benign-missense-rate evidence was supplied.	pvs1_gene_context clinvar
PP3	Met	Met, strong: missense REVEL score 0.955 meets the PP3 strong threshold of >=0.932.	revel
PP4	Not assessed	Not assessed: the case lacks a documented patient phenotype or family history demonstrating a highly specific single-gene disease presentation.
PP5	Not met	Not met: the exact-variant ClinVar record has 0 expert-panel submissions, and its Pathogenic/Likely pathogenic assertions are clinical-laboratory submissions.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its frequency is not >=0.05, the generic BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed allele, so the frequency is below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD absence does not document the required healthy-adult genotype observation for BS2.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: two exact-variant assays reported disrupted or completely abolished Smad2-Smad4 complex formation rather than preserved protein function.	PMID:11274206 PMID:11779503
BS4	Not assessed	Not assessed: no tested affected relatives are documented as lacking SMAD4 c.1082G>A, so non-segregation cannot be evaluated.
BP1	Not assessed	Not assessed: loss-of-function evidence exists, but a primarily truncating SMAD4 disease spectrum was not established.	pvs1_gene_context PMID:15014009
BP2	Not assessed	Not assessed: no pathogenic partner variant or parent/offspring phase result establishes the required trans or cis relationship for NM_005359.6:c.1082G>A.	cspec
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 score 0.955 exceeds the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no affected case is documented with an alternate molecular basis that explains the disease instead of SMAD4 p.Arg361His.
BP6	Not met	Not met: the exact-variant ClinVar audit has no benign expert-panel classification and instead contains Pathogenic/Likely 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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