Classification rationale

PM2 VUS

SMAD4 c.463A>G missense · exon 5

VUS: PM2 (supporting) is met because the gnomAD v4.1 maximum observed subpopulation allele frequency is 2.23e-05, below 0.0001.

PM2 → VUS

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_005359.6 · variants mapped to exon structure

SMAD4 NM_005359.6

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 22 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v4.1 all-comers allele frequency 1.88e-06 (3/1,594,076) and popmax 2.23e-05 are both below the 0.0001 PM2 threshold.

gnomAD v4.1 all-comers: total AF 1.88197e-06 (3/1,594,076 alleles), homozygotes 0; exome AF 2.08085e-06 (3/1,441,718); genome cohort contributed 0 alleles.gnomAD v2.1 all-comers (exome only): total AF 3.9781e-06 (1/251,376 alleles), homozygotes 0.gnomAD v2.1 exomes-only NON_CANCER subset: AF 4.2223e-06 (1/236,838 alleles), homozygotes 0.

gnomad_v2 ↗gnomad_v4 ↗clinvar ↗PMID:25741868 ↗

Assessed · not applied · 14 not met · 8 not assessed

Pathogenic

PS1 Not met: no established pathogenic variant shares this p.Ser155Gly change, and c.463A>G is the only nucleotide change at codon 155 that can encode glycine.

PS2 Not assessed: no documented proband-parent testing or confirmed de novo result is available for NM_005359.6:c.463A>G.

PS3 Not met: no functional study tested c.463A>G, and the 12-variant SMAD4 reporter assay panel (PMID:40835297) excludes it.

PS4 Not assessed: no exact-variant case-control enrichment, affected-case count, odds ratio, or statistically supported excess was available.

PM1 Not met: residue 155 is not a statistically significant mutational hotspot and no approved SMAD4 critical-domain table or pathogenic codon-155 variant places it in a functional domain.

PM5 Not met: the three alternative codon-155 missense variants (p.Ser155Asn, p.Ser155Thr, p.Ser155Arg) are all classified Uncertain significance, so no pathogenic same-residue comparator exists.

PM6 Not assessed: no affected proband with presumed de novo inheritance and unavailable or untested parents is documented for this variant.

PP1 Not assessed: no affected relatives, informative meioses, or family cosegregation data are documented for NM_005359.6:c.463A>G.

PP2 Not met: although SMAD4 is missense-constrained (gnomAD mis_z 6.18), only 29 of 371 pathogenic/likely pathogenic ClinVar records (8%) are missense, so missense is not a common mechanism.

PP3 Not met: missense REVEL 0.484 is below the ClinGen SVI PP3 supporting threshold of >=0.644.

PP4 Not assessed: no individual-level phenotype sufficiently specific for a SMAD4-associated disorder was provided for this variant carrier.

PP5 Not met: the exact ClinVar record has zero expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.

Benign

BA1 Not met: the highest gnomAD subpopulation allele frequency, 2.23e-05, is about three orders of magnitude below the 0.05 BA1 stand-alone threshold.

BS1 Not met: the highest observed allele frequency, 2.23e-05, is more than two orders of magnitude below the 0.01 BS1 threshold (Whiffin 2017).

BS2 Not met: zero homozygotes for c.463A>G in any gnomAD dataset (v2.1 and v4.1), and SMAD4 disease is not fully penetrant at an early age.

BS3 Not met: no functional assay tested c.463A>G, so preserved BMP/TGF-beta signalling for p.(Ser155Gly) is unproven, not demonstrated.

BS4 Not assessed: no informative unaffected relatives with documented negative testing and adequate phenotype assessment are available for BS4.

BP1 Not met: 29 of 371 pathogenic/likely pathogenic SMAD4 ClinVar records are missense, so SMAD4 disease is not caused by truncating variants alone and BP1 does not apply.

BP2 Not assessed: no documented phase, cis/trans relationship, or second pathogenic variant is available for this SMAD4 c.463A>G observation.

BP4 Not met: missense REVEL 0.484 exceeds the ClinGen SVI BP4 supporting threshold of <=0.29.

BP5 Not assessed: no exact-variant affected case with a documented alternate molecular basis for disease was identified.

BP6 Not met: the exact ClinVar Likely benign assertion is from a single laboratory, with zero expert-panel submissions.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.88197e-06; MAF= 0.00019%, 3/1594076 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23105e-05; MAF= 0.00223%, 1/44822 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 3.9781e-06; MAF= 0.00040%, 1/251376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79786e-06; MAF= 0.00088%, 1/113664 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,594,076
0 hom

East Asian 1 / 44,822	0.0022%
African/African American 1 / 74,706	0.0013%
European (non-Finnish) 1 / 1,161,556	8.6e-05%

+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0004% · 1 / 251,376
0 hom

European (non-Finnish)

1 / 113,664

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 Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 374977)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.484. BayesDel score = -0.242868.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMAD4, a transcription factor in the TGFß pathway, is frequently mutated in pancreatic and colorectal cancers.

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. 6 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ 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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

20301299 ↗ Heritable Thoracic Aortic Disease Overview. CLINVAR

20301642 ↗ Juvenile Polyposis Syndrome. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389505 ↗ Genetics of Colorectal Cancer (PDQ®): Health Professional Version. CLINVAR

28655553 ↗ Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. CLINVAR

35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

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