About SMAD4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMAD4 c.1082G>A, p.(Arg361His)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 8
Benign evidence criteria: 0
Pathogenic criteria applied · 8
PS3Strong
PS3 · strong
R361H was directly tested in two independent publications and demonstrated complete disruption of Smad2-Smad4 heterodimer formation and loss of TGF-beta-dependent transcriptional activity. In PMID:11274206, recombinant R361H Smad4 protein failed to form a heterodimer with Smad2 in gel filtration and electrophoretic mobility shift assays. In PMID:17132729, R361H abolished interaction with phosphorylated R-Smads and lost TGF-beta-responsive transcriptional activity in a reporter assay. Both findings are consistent with loss of SMAD4 tumor-suppressor function.
PS4Moderate
PS4 · moderate
This variant has been reported as pathogenic by 5 independent clinical laboratories and as likely pathogenic by 1 laboratory in ClinVar (Variation ID 24832, 2-star review status). Reported clinical conditions include juvenile polyposis syndrome, JPS/HHT syndrome, and hereditary cancer-predisposing syndrome. The variant is listed in PMID:15014009 Table 2 as occurring in colorectal cancer. Multiple independent clinical observations support an increased prevalence in affected individuals.
PM1Moderate
PM1 · moderate
Residue Arg361 lies within the MH2 domain mutation cluster region (MCR, codons 330-370), a well-established mutational hot spot critical for Smad protein heterodimerization. PMID:15014009 characterized this MCR as containing 53% of all missense mutations in the MH2 domain. Cancerhotspots.org confirms this residue as a statistically significant hotspot. The loop-helix region of the MH2 domain is essential for Smad2-Smad4 heterocomplex formation and TGF-beta signaling.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD-Canada v1.0. gnomAD v2.1 and v4.1 data were not captured due to scrape timeout. Absence from population databases supports rarity consistent with a pathogenic variant.
PM5Supporting
PM5 · supporting
Different pathogenic missense changes at the same residue (Arg361) have been reported in the literature: R361C (CGC>TGC) in juvenile polyposis syndrome (refs 25-27 in PMID:15014009), R361S (CGC>AGC) in colorectal cancer, and R361W (CGG>TGG) in duodenal cancer. The automated PM5 candidate harvest did not identify ClinVar comparator variants, but the literature supports multiple pathogenic amino acid changes at this residue.
PP3Supporting
PP3 · supporting
Multiple in silico predictors support a deleterious effect: REVEL score of 0.955 (strongly damaging, well above the 0.9 threshold) and BayesDel score of 0.578 (damaging). SpliceAI delta score of 0.08 predicts no significant splicing impact, consistent with a missense effect at the protein level.
PP4Supporting
PP4 · supporting
The variant has been reported in patients with clinical presentations highly specific for SMAD4-related disease, including juvenile polyposis syndrome, JPS/HHT overlap syndrome, and hereditary cancer-predisposing syndrome. The ClinVar conditions list includes these well-defined phenotypes with high specificity for SMAD4 pathogenic variants.
PP5Supporting
PP5 · supporting
The variant is classified as Pathogenic in ClinVar (Variation ID 24832) by 5 clinical laboratories and as Likely pathogenic by 1 laboratory, with a 2-star review status ('criteria provided, multiple submitters, no conflicts'). Multiple reputable clinical laboratories have independently reached the same classification.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 moderate, PM1 moderate, PM2 supporting, PM5 supporting, PP3 supporting, PP4 supporting, PP5 supporting; combination = 1 strong + 2 moderate + 5 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.080 maximum delta
Recorded SpliceAI maximum delta score: 0.080. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
6 reported laboratory submissions
5 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
261 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61684056, n = 261 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 8 met · 16 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005359.5:c.1082G>A (p.Arg361His) is a missense variant in exon 9 of SMAD4, located within the MH2 domain mutation cluster region (codons 330-370) critical for Smad protein heterodimerization and TGF-beta signaling.
This variant is absent from gnomAD-Canada v1.0 population data (PM2_Supporting).
Multiple in silico predictors support a deleterious effect, including a REVEL score of 0.955 and BayesDel score of 0.578 (PP3).
Residue Arg361 lies within the MH2 domain mutation cluster region (MCR, codons 330-370), a well-established mutational hot spot containing the majority of SMAD4 missense mutations in human tumors. Cancerhotspots.org confirms this residue as a statistically significant hotspot (PM1).
Functional studies demonstrate that R361H disrupts Smad2-Smad4 heterodimer formation in vitro (PMID:11274206) and abolishes TGF-beta-dependent transcriptional activity in reporter assays (PMID:17132729). Both findings are consistent with loss of SMAD4 tumor-suppressor function (PS3).
Different pathogenic missense changes at the same residue have been reported: R361C in juvenile polyposis syndrome and R361S/R361W in colorectal and duodenal cancers (PM5_Supporting).
The variant has been reported as Pathogenic by 5 independent clinical laboratories and as Likely pathogenic by 1 laboratory in ClinVar (Variation ID 24832, 2-star review status) in individuals with juvenile polyposis syndrome, JPS/HHT overlap syndrome, and hereditary cancer-predisposing syndrome (PS4_Moderate, PP5, PP4).
The variant has been observed in colorectal cancer in the published literature (PMID:15014009 Table 2). COSMIC reports this variant in 261 somatic cancer samples, consistent with its role as a recurrent pathogenic alteration.
No criteria match.
Met · 8
PS3 StrongR361H was directly tested in two independent publications and demonstrated complete disruption of Smad2-Smad4 heterodimer formation and loss of TGF-beta-dependent transcriptional activity. In PMID:11274206, recombinant R361H Smad4 protein failed to form a heterodimer with Smad2 in gel filtration and electrophoretic mobility shift assays. In PMID:17132729, R361H abolished interaction with phosphorylated R-Smads and lost TGF-beta-responsive transcriptional activity in a reporter assay. Both findings are consistent with loss of SMAD4 tumor-suppressor function. Details ▾Hide ▴
Evidence considered
- PMID:11274206: R361H directly tested
- disrupts Smad2-Smad4 heterodimer formation in vitro (gel filtration
- EMSA)
- PMID:17132729: R361H directly tested
- abolishes interaction with phosphorylated Smad2
- loses TGF-beta-dependent reporter activity
- PMID:11779503: R361H confirmed to abolish Smad2-Smad4 complex in phosphorylated context
- OncoKB: Loss-of-function biological effect
- Likely Oncogenic
Sources
PS4 ModerateThis variant has been reported as pathogenic by 5 independent clinical laboratories and as likely pathogenic by 1 laboratory in ClinVar (Variation ID 24832, 2-star review status). Reported clinical conditions include juvenile polyposis syndrome, JPS/HHT syndrome, and hereditary cancer-predisposing syndrome. The variant is listed in PMID:15014009 Table 2 as occurring in colorectal cancer. Multiple independent clinical observations support an increased prevalence in affected individuals. Details ▾Hide ▴
Evidence considered
- ClinVar 24832: Pathogenic (5 labs)
- Likely pathogenic (1 lab)
- 2-star review
- Conditions: JPS
- JPS/HHT
- hereditary cancer-predisposing syndrome
- colorectal cancer
- PMID:15014009 Table 2: R361H (CGC>CAC) listed in colorectal cancer
Still missing
- Formal case-control statistics not available
- Individual patient counts and phenotypes from primary literature not extracted
Sources
PM1 ModerateResidue Arg361 lies within the MH2 domain mutation cluster region (MCR, codons 330-370), a well-established mutational hot spot critical for Smad protein heterodimerization. PMID:15014009 characterized this MCR as containing 53% of all missense mutations in the MH2 domain. Cancerhotspots.org confirms this residue as a statistically significant hotspot. The loop-helix region of the MH2 domain is essential for Smad2-Smad4 heterocomplex formation and TGF-beta signaling. Details ▾Hide ▴
Evidence considered
- Residue 361 is within the MH2 MCR (codons 330-370) per PMID:15014009
- Cancerhotspots.org: statistically significant hotspot at R361
- MH2 loop-helix region is critical for Smad heterodimerization and TGF-beta signaling
Sources
PM2 SupportingThe variant is absent from gnomAD-Canada v1.0. gnomAD v2.1 and v4.1 data were not captured due to scrape timeout. Absence from population databases supports rarity consistent with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada v1.0 (0/0 alleles)
- gnomAD v2.1 and v4.1: data unavailable (scrape timeout)
Still missing
- gnomAD v2.1 and v4.1 allele frequency data not captured
Sources
PM5 SupportingDifferent pathogenic missense changes at the same residue (Arg361) have been reported in the literature: R361C (CGC>TGC) in juvenile polyposis syndrome (refs 25-27 in PMID:15014009), R361S (CGC>AGC) in colorectal cancer, and R361W (CGG>TGG) in duodenal cancer. The automated PM5 candidate harvest did not identify ClinVar comparator variants, but the literature supports multiple pathogenic amino acid changes at this residue. Details ▾Hide ▴
Evidence considered
- R361C (CGC>TGC) reported in JPS (refs 25-27 in PMID:15014009)
- R361S (CGC>AGC) reported in colorectal cancer
- R361W (CGG>TGG) reported in duodenal cancer (PX255)
- All are different amino acid changes at the same residue
Still missing
- No formal ClinVar pathogenic classification for comparator variants at codon 361
- pm5_candidates.json did not harvest automated candidates
Sources
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score of 0.955 (strongly damaging, well above the 0.9 threshold) and BayesDel score of 0.578 (damaging). SpliceAI delta score of 0.08 predicts no significant splicing impact, consistent with a missense effect at the protein level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.955 (strongly damaging)
- BayesDel: 0.578 (damaging)
- SpliceAI max delta: 0.08 (no splice impact)
Sources
PP4 SupportingThe variant has been reported in patients with clinical presentations highly specific for SMAD4-related disease, including juvenile polyposis syndrome, JPS/HHT overlap syndrome, and hereditary cancer-predisposing syndrome. The ClinVar conditions list includes these well-defined phenotypes with high specificity for SMAD4 pathogenic variants. Details ▾Hide ▴
Evidence considered
- ClinVar conditions: JPS
- JPS/HHT syndrome
- hereditary cancer-predisposing syndrome
- These are phenotypes with high specificity for SMAD4-related disease
Sources
PP5 SupportingThe variant is classified as Pathogenic in ClinVar (Variation ID 24832) by 5 clinical laboratories and as Likely pathogenic by 1 laboratory, with a 2-star review status ('criteria provided, multiple submitters, no conflicts'). Multiple reputable clinical laboratories have independently reached the same classification. Details ▾Hide ▴
Evidence considered
- ClinVar 24832: Pathogenic (5 labs)
- Likely pathogenic (1 lab)
- 2-star review: criteria provided
- multiple submitters
- no conflicts
- Submitters include LabCorp
- Invitae
- GeneDx
- Ambry Genetics
- Fulgent Genetics
Sources
Not met · 16 · evaluated, threshold not reached
PVS1 NM_005359.5:c.1082G>A is a missense variant (p.Arg361His) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical splice consensus variants recognized by generic PVS1 (PMC6185798). SMAD4 loss of function is the established disease mechanism for JPS/HHT, but missense variants are not captured by the default PVS1 framework. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg361His)
- not a null variant
- pvs1_variant_assessment: variant_bucket='other'
- apply_generic_pvs1_framework=false
- SMAD4 LOF mechanism supported by germline literature (JPS/HHT)
Sources
PS1 No alternative nucleotide change at codon 361 producing the same amino acid substitution (p.Arg361His) has been identified. The c.1082G>A variant represents the canonical nucleotide change for Arg361His. Details ▾Hide ▴
Evidence considered
- No evidence of a different nucleotide change producing the same Arg361His substitution
PS2 No de novo occurrence data for this variant was identified in the case materials or reviewed literature. Details ▾Hide ▴
Still missing
- No de novo reports available
PM6 No de novo observation data was identified in the case materials or reviewed literature. PM6 requires specific de novo confirmation for this variant. Details ▾Hide ▴
Still missing
- No de novo reports available
PP1 No segregation data was identified in the case materials or reviewed literature. Details ▾Hide ▴
Still missing
- No family segregation data available
PP2 HCI prior data is not available for SMAD4, precluding calculation of the missense constraint z-score. Without gene-level constraint data, PP2 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- HCI prior not found for SMAD4
Still missing
- HCI prior/probability data unavailable for SMAD4
BA1 The variant is absent from gnomAD-Canada v1.0 and not observed at allele frequency greater than 1% in any population database. Does not meet BA1 threshold. Details ▾Hide ▴
BS1 The variant is absent from gnomAD-Canada v1.0. No population frequency data supports an allele frequency above 0.3%. Does not meet BS1 threshold. Details ▾Hide ▴
BS2 No evidence of this variant observed in healthy adults in the homozygous or hemizygous state, nor in a sufficiently large control cohort. Does not meet BS2 threshold. Details ▾Hide ▴
Still missing
- No healthy control data available
BS3 All functional studies identified demonstrate a damaging effect: R361H disrupts Smad2-Smad4 heterodimer formation (PMID:11274206) and abolishes TGF-beta-dependent signaling (PMID:17132729). These findings support pathogenicity, not benign effect. BS3 is not met. Details ▾Hide ▴
Evidence considered
- All functional evidence demonstrates loss of function
- supporting pathogenicity
- No studies show normal or benign functional effect
Sources
BS4 No segregation data demonstrating lack of cosegregation with disease was identified in the case materials or reviewed literature. Details ▾Hide ▴
Still missing
- No family segregation data available
BP1 While SMAD4 disease is associated with truncating variants, missense variants in the MH2 domain mutation cluster region (codons 330-370) are a well-established pathogenic mechanism. BP1 specifically applies when a missense variant occurs in a gene where only truncating variants cause disease. This is not the case for SMAD4, as missense variants in the MH2 MCR are recurrently observed in JPS, colorectal cancer, and other SMAD4-related conditions. Details ▾Hide ▴
Evidence considered
- SMAD4 has both missense and truncating pathogenic variants
- MH2 MCR (codons 330-370) is a well-characterized hot spot for pathogenic missense mutations
- R361H is specifically listed as a recurrent mutation in PMID:15014009
Sources
BP2 No evidence of this variant observed in trans with a known pathogenic variant was identified in the case materials or reviewed literature. Details ▾Hide ▴
Still missing
- No trans-configuration data available
BP4 Multiple in silico predictors conflict with a benign interpretation: REVEL score of 0.955 strongly predicts damaging effect, and BayesDel score of 0.578 is consistent with pathogenicity. These scores do not support benign computational evidence. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL: 0.955 (damaging
- not benign)
- BayesDel: 0.578 (damaging
Sources
revelbayesdel
BP5 No evidence of an alternative molecular cause explaining the patient's phenotype was identified in the case materials or reviewed literature. Details ▾Hide ▴
Still missing
- No alternative molecular diagnosis data available
BP6 The variant is classified as Pathogenic in ClinVar by multiple clinical laboratories. No reputable source classifies this variant as benign or likely benign. BP6 is not met. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PS5 PS5 was not in the assessment list per the case instructions. This criterion is variably applied across frameworks. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ASMAD4-related disorders (JPS, HHT) are autosomal dominant; PM3 (detected in trans with a pathogenic variant) is not applicable in this inheritance context. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a single-nucleotide substitution, not a protein-length-altering change (in-frame deletion/insertion, stop-loss). PM4 applies to non-repeat-region protein-length changes. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AVariant is a missense substitution, not an in-frame indel. BP3 applies to in-frame deletions/insertions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_005359.5:c.1082G>A is a missense variant (p.Arg361His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SMAD4
- Transcript
- NM_005359.5
- Coding (HGVS c.)
- NM_005359.5:c.1082G>A
- Protein (HGVS p.)
- NP_005350.1:p.(Arg361His)
- GRCh38
- chr18:51065549 G>A
- GRCh37
- chr18:48591919 G>A
- ClinVar
- 24832
- COSMIC
- COSV61684056
Gene diagram
Every interpreted variant in SMAD4, mapped onto the exon structure of NM_005359.5. Select a row to find it on the plot.
SMAD4NM_005359.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SMAD4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.955
- BayesDel
- 0.578
How the predictions were used
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score of 0.955 (strongly damaging, well above the 0.9 threshold) and BayesDel score of 0.578 (damaging). SpliceAI delta score of 0.08 predicts no significant splicing impact, consistent with a missense effect at the protein level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.955 (strongly damaging)
- BayesDel: 0.578 (damaging)
- SpliceAI max delta: 0.08 (no splice impact)
Sources
BP4 Multiple in silico predictors conflict with a benign interpretation: REVEL score of 0.955 strongly predicts damaging effect, and BayesDel score of 0.578 is consistent with pathogenicity. These scores do not support benign computational evidence. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL: 0.955 (damaging
- not benign)
- BayesDel: 0.578 (damaging
Sources
revelbayesdel
BP7 N/ANM_005359.5:c.1082G>A is a missense variant (p.Arg361His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.955. BayesDel score = 0.578234.
6 paper records listed. 5 cited in the classification.
Cited in the classification
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PMID 11274206 ↗Formation of a stable heterodimer between Smad2 and Smad4.Wu JW et al. · 2001 Jun 8R361H mutation in Smad4 was generated as a recombinant protein and directly tested for heterodimer formation with Smad2. The mutation completely disrupted Smad2-Smad4 heterodimer formation in gel filtration and electrophoretic mobility shift assays, demonstrating loss of the protein interaction required for TGF-beta signaling.→ PS3 → PM1 Names this variant
Source detail
Each of the three tumor-derived mutations in Smad4 (D351H, R361H, and V370D), as well as their corresponding mutations in Smad2 (D300H, R310H, and V319D), disrupted the formation of a heterocomplex (Table II; Fig. 4A).
Location Results, Table II; Figure 4
Context Gel filtration chromatography and electrophoretic mobility shift assay; recombinant Smad2 (241-467) and Smad4 (251-552) proteins purified from E. coli
-
PMID 11779503 ↗Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.R361H in Smad4, along with D351H, was shown to completely abolish the formation of the Smad2-Smad4 complex in the context of phosphorylated Smad2. This was part of a systematic mutagenesis analysis of the phosphoserine-mediated heterocomplex interface, confirming that mutations in the loop-helix region disrupt TGF-beta signaling complex assembly.→ PS3 Names this variant
Source detail
Two mutations affecting residues in the loop-helix region of Smad4, D351H and R361H, completely abolished the formation of the Smad2-Smad4 complex.
Location Results, pp. 1283-1284; Table 2
Context Gel filtration analysis of phosphorylated Smad2 homotrimers with Smad4-MH2; recombinant proteins
-
PMID 15014009 ↗Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors.Iacobuzio-Donahue CA et al. · 2004 Mar 1Codon 361 is identified within the MH2 mutation cluster region (MCR, codons 330-370), a statistically significant mutational hot spot. R361H (CGC>CAC) is listed in Table 2 as occurring in colorectal cancer. The MCR corresponds to the loop-helix region critical for Smad intermolecular interactions. Mutations within the MCR can retain Madh4 protein expression and nuclear localization, suggesting alternative functional consequences distinct from protein degradation.→ PS4 → PM1 → PM5 Names this variant
Source detail
Missense mutations affecting codon 361 were reported in three colorectal cancers (22, 41, 42), syndromic juvenile polyps (25-27), and a small intestinal cancer (37) in addition to a duodenal cancer xenograft reported in the current study (PX255).
Location Results, Table 2; Figure 1; Discussion
Context Mutational spectrum analysis across tumor types; immunohistochemistry of 9 cancers with missense mutations
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PMID 17132729 ↗Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling.Lim SK et al. · 2006 Dec 5Smad4R361H was directly tested in a c-myc reporter assay in Smad4-null MDA-MB-468 cells. The mutant retained TGF-beta-independent c-myc promoter activation (cooperating with LEF1) but completely lost TGF-beta-dependent transcriptional responses, having abolished interaction with phosphorylated R-Smads. The dual effect demonstrates selective loss of tumor-suppressive TGF-beta signaling while retaining an alternative transcriptional function.→ PS3 Names this variant
Source detail
When wild-type Smad4, Smad4D351H, or Smad4R361H proteins were expressed in Smad4-null MDA-MB-468 cells with the TGF-beta-responsive SBE12 reporter, only the wild-type Smad4 protein could restore the TGF-beta response.
Location Results, paragraphs 'Tumor-Derived Smad4 Mutants...' and Figure 4b
Context Luciferase reporter assay, Smad4-null MDA-MB-468 breast cancer cells; SBE12 TGF-beta-responsive reporter and TIEm myc reporter
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PMID 27595937 ↗Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.R361H and D351H Smad4 mutant constructs were used to demonstrate that disruption of Smad4 interaction with phosphorylated R-Smads abolished BMP/TGF-beta-dependent regulation of heparanase expression in neuroblastoma cells. Transfection of R361H did not affect the expression levels or promoter activity of HPSE, confirming that the SMAD4-HPSE regulatory axis requires intact R-Smad interaction.→ PS3 Names this variant
Source detail
transfection of D351H and R361H, two Smad4 constructs with mutation of the loop-helix region, abolished the interaction of Smad4 with R-Smads, phosphorylated Smad1 and Smad2 (p-Smad1 and p-Smad2), in these NB cells.
Location Results, paragraph 'Smad4 represses the expression of HPSE in cultured NB cell lines'; Supplementary Fig. S3c-f
Context Co-immunoprecipitation and western blot in IMR32 and BE(2)-C neuroblastoma cells; HPSE promoter luciferase reporter
Other recorded publications
-
PMID 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.ACMG/AMP standards and guidelines for interpretation of sequence variants. General methodological reference that does not mention NM_005359.5:c.1082G>A or any specific SMAD4 variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.080
Open source ↗
ClinVar
5 Pathogenic · 1 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/24832/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-48591919-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-51065549-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/18-51065549-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005359.5%3Ac.1082…
- OncoKB ↗www.oncokb.org/gene/SMAD4/R361H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128485309
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 24832)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.955. BayesDel score = 0.578234.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61684056, n = 261 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.