About SMAD4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMAD4 c.1081C>G, p.(Arg361Gly)
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: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS2Strong
PS2 · strong
De novo occurrence confirmed in a proband with juvenile polyposis and hereditary hemorrhagic telangiectasia (JP-HHT overlap syndrome). The variant (c.1081C>G, p.Arg361Gly) was absent from both unaffected parents in Family 230. Chromosome 18 haplotype analysis confirmed biological parentage (PMID:15031030). Phenotype is highly specific for SMAD4-related disease.
PS4Moderate
PS4 · moderate
The variant has been observed in at least 2-3 unrelated probands with juvenile polyposis syndrome (JPS) and/or JPS-HHT overlap syndrome. PMID:15031030 reports c.1081C>G de novo in Family 230 (JP/HHT). PMID:18823382 lists c.1081C>G (R361G) in sporadic proband JP71 with JPS. PMID:22316667 confirms two patients in the JP database shared substitutions at nucleotide 1081. Observed prevalence in affected individuals is significant given the rarity of JPS.
PM1Moderate
PM1 · moderate
Located in a well-established functional domain and a statistically significant mutational hotspot. The variant lies within the MH2 domain (codons 323-552) and specifically within Mutational Rich Region 1 (MRR1, codons 330-370), the most frequently mutated region of SMAD4. The MH2 domain mediates protein-protein interactions with R-SMADs and transcriptional activity (PMID:18823382). Hotspot analysis confirmed statistical significance at this residue.
PM2Moderate
PM2 · moderate
Absent from all population databases. No allele count observed in gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), or gnomAD-Canada v1.0 (genomes). Allele frequency is 0.00, well below the PM2 threshold of <0.1%.
PP3Supporting
PP3 · supporting
Multiple lines of computational evidence support a deleterious effect. REVEL score 0.885 (strongly damaging, well above 0.75 threshold). The variant lies within the highly conserved MH2 domain at a residue within a statistically significant mutational hotspot. SpliceAI predicts no cryptic splice impact (max delta 0.05), consistent with a pure missense mechanism. BayesDel score 0.512 provides additional, though weaker, supporting evidence.
PP4Supporting
PP4 · supporting
The phenotype of the proband harboring this variant is highly specific for SMAD4-related disease. The affected individual (PMID:15031030, Family 230, II-2) presented with both juvenile polyposis (multiple colonic polyps, anemia) and hereditary hemorrhagic telangiectasia (telangiectases, epistaxis), the characteristic JP-HHT overlap syndrome specifically associated with SMAD4 mutations rather than ENG or ACVRL1 mutations.
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: PS2 strong, PS4 moderate, PM1 moderate, PM2 moderate, PP3 supporting, PP4 supporting; combination = 1 strong + 3 moderate + 2 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
15 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61686083, n = 15 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.
27 criteria with recorded statuses: 6 met · 12 not met · 4 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
De novo occurrence confirmed in a proband with juvenile polyposis and hereditary hemorrhagic telangiectasia overlap syndrome; variant absent from both unaffected parents with paternity and maternity confirmed by haplotype analysis.
Observed in at least 2-3 unrelated probands with juvenile polyposis syndrome, representing a significantly increased prevalence in affected individuals compared to the general population.
Located within the MH2 domain (Mutational Rich Region 1), a well-established functional domain and statistically significant mutational hotspot in SMAD4.
Absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, with allele frequency of zero in all populations.
REVEL score of 0.885 strongly predicts a deleterious effect; SpliceAI confirms no cryptic splice alteration (max delta 0.05), consistent with a missense mechanism.
Proband phenotype (colonic juvenile polyps, anemia, telangiectases, epistaxis) is highly specific for the SMAD4-associated JP-HHT overlap syndrome.
No criteria match.
Met · 6
PS2 StrongDe novo occurrence confirmed in a proband with juvenile polyposis and hereditary hemorrhagic telangiectasia (JP-HHT overlap syndrome). The variant (c.1081C>G, p.Arg361Gly) was absent from both unaffected parents in Family 230. Chromosome 18 haplotype analysis confirmed biological parentage (PMID:15031030). Phenotype is highly specific for SMAD4-related disease. Details ▾Hide ▴
Evidence considered
- Confirmed de novo variant in proband II-2 (Family 230). Mutation absent from both unaffected parents. Paternity and maternity confirmed by chromosome 18 haplotypes. Proband presented with colonic juvenile polyps
- telangiectases
- and epistaxis consistent with JP-HHT overlap syndrome.
Sources
PS4 ModerateThe variant has been observed in at least 2-3 unrelated probands with juvenile polyposis syndrome (JPS) and/or JPS-HHT overlap syndrome. PMID:15031030 reports c.1081C>G de novo in Family 230 (JP/HHT). PMID:18823382 lists c.1081C>G (R361G) in sporadic proband JP71 with JPS. PMID:22316667 confirms two patients in the JP database shared substitutions at nucleotide 1081. Observed prevalence in affected individuals is significant given the rarity of JPS. Details ▾Hide ▴
Evidence considered
- Proband JP71 (sporadic JPS) with c.1081C>G (PMID:18823382
- Table 1). Proband II-2 (JP-HHT
- Family 230) with de novo c.1081C>G (PMID:15031030). Two patients with nucleotide 1081 substitutions in the JP database of 119 probands (PMID:22316667).
Still missing
- Exact count of unrelated probands harboring c.1081C>G across all published cohorts not comprehensively aggregated.
Sources
PM1 ModerateLocated in a well-established functional domain and a statistically significant mutational hotspot. The variant lies within the MH2 domain (codons 323-552) and specifically within Mutational Rich Region 1 (MRR1, codons 330-370), the most frequently mutated region of SMAD4. The MH2 domain mediates protein-protein interactions with R-SMADs and transcriptional activity (PMID:18823382). Hotspot analysis confirmed statistical significance at this residue. Details ▾Hide ▴
Evidence considered
- Variant lies in MH2 domain MRR1 (exon 8
- nucleotides 989-1139)
- which contains 25% of all reported SMAD4 mutations. Residue 361 is within the codon 330-370 mutational hotspot. Hotspot analysis confirms statistically significant clustering at this residue.
Sources
PM2 ModerateAbsent from all population databases. No allele count observed in gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), or gnomAD-Canada v1.0 (genomes). Allele frequency is 0.00, well below the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: allele count 0
- allele frequency 0.00. gnomAD v4.1: allele count 0
- allele frequency 0.00. gnomAD-Canada v1.0: allele count 0
- allele frequency 0.00.
Sources
PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score 0.885 (strongly damaging, well above 0.75 threshold). The variant lies within the highly conserved MH2 domain at a residue within a statistically significant mutational hotspot. SpliceAI predicts no cryptic splice impact (max delta 0.05), consistent with a pure missense mechanism. BayesDel score 0.512 provides additional, though weaker, supporting evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.885 (damaging). BayesDel: 0.512. SpliceAI max delta: 0.05 (no splice impact
- consistent with missense mechanism). Residue in statistically significant hotspot within conserved MH2 domain.
Sources
PP4 SupportingThe phenotype of the proband harboring this variant is highly specific for SMAD4-related disease. The affected individual (PMID:15031030, Family 230, II-2) presented with both juvenile polyposis (multiple colonic polyps, anemia) and hereditary hemorrhagic telangiectasia (telangiectases, epistaxis), the characteristic JP-HHT overlap syndrome specifically associated with SMAD4 mutations rather than ENG or ACVRL1 mutations. Details ▾Hide ▴
Evidence considered
- Proband II-2 presented with colonic juvenile polyps
- anemia
- telangiectases
- and epistaxis — the JP-HHT overlap syndrome pathognomonic for SMAD4-related disease.
Sources
Not met · 12 · evaluated, threshold not reached
PS3 No variant-specific functional assay has been performed for NM_005359.5:c.1081C>G (p.Arg361Gly). PMID:22316667 studied the functional impact of SMAD4 mutations on BMP signaling but assessed c.1081C>A (p.Arg361Ser), not c.1081C>G. OncoKB curation of Likely Oncogenic / Likely Loss-of-function is a literature-derived inference, not direct experimental evidence for this variant. Details ▾Hide ▴
Evidence considered
- Functional study at same residue (R361S) showed 8% reduction in BMP signaling (not statistically significant)
- but did not assess R361G.
Still missing
- No luciferase reporter
- BMP signaling
- or other functional assay performed for c.1081C>G (p.Arg361Gly) specifically.
Sources
BA1 Variant is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency is 0.00, well below the BA1 threshold of >1% (non-VCEP). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00. gnomAD v4.1 AF: 0.00. gnomAD-Canada AF: 0.00. All below BA1 >1% threshold.
Sources
BS1 Variant is absent from all population databases. Allele frequency is 0.00, below the BS1 threshold of >0.3% (non-VCEP). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00. gnomAD v4.1 AF: 0.00. gnomAD-Canada AF: 0.00. All below BS1 >0.3% threshold.
Sources
BS2 Variant is absent from population databases. No observation in healthy adult controls to suggest this variant occurs in the general population without disease. JP/HHT is an adult-onset disorder with age-dependent penetrance, but zero population observations do not support BS2. Details ▾Hide ▴
Evidence considered
- Zero observations in gnomAD across all populations and age groups.
Sources
BS3 No well-established functional studies demonstrate a neutral or benign effect. The only functional study at the same residue (c.1081C>A, p.Arg361Ser, PMID:22316667) showed an 8% reduction in BMP signaling that was not statistically significant, but this does not constitute evidence of a benign effect for c.1081C>G. The somatic observation of R361G as a stable mutation in ovarian low-grade serous carcinoma (PMID:25523272) is consistent with a functional role in tumorigenesis. Details ▾Hide ▴
Evidence considered
- No benign functional evidence. Somatic R361G in ovarian LGSC (PMID:25523272) suggests functional significance rather than neutrality.
Still missing
- No functional assay directly testing c.1081C>G (p.Arg361Gly) for neutral effect.
Sources
BS4 No evidence of non-segregation with disease. The only family data available (PMID:15031030) shows the variant arose de novo in an affected proband with no affected relatives, which does not provide non-segregation evidence. Details ▾Hide ▴
Evidence considered
- De novo event in affected proband
- no non-segregation observed.
Sources
BP1 Although BP1 is intended for missense variants in genes where truncating variants are the primary mechanism of disease, missense variants in the MH2 domain of SMAD4 are a well-established pathogenic mechanism in JPS and JP-HHT. Multiple pathogenic missense variants in this domain have been reported (PMID:18823382, PMID:15031030). Details ▾Hide ▴
Evidence considered
- Missense variants in SMAD4 MH2 domain are a well-documented cause of JPS and JP-HHT syndrome. BP1 does not apply when missense variants are a recognized disease mechanism.
Sources
BP2 No observation of this variant in trans with a known pathogenic SMAD4 variant. SMAD4-related disorders (JPS, HHT, JP-HHT) are autosomal dominant with hapoinsufficiency as the disease mechanism; observation in trans is not expected and BP2 does not apply. Details ▾Hide ▴
Evidence considered
- Autosomal dominant disorder
- BP2 (observation in trans with a pathogenic variant) is not applicable to the disease mechanism.
BP4 Multiple in silico tools predict a deleterious effect. REVEL score 0.885 is strongly in the damaging range (>0.75). SpliceAI predicts no splice impact (max delta 0.05), which is consistent with a missense mechanism rather than a benign indication. Computational evidence supports pathogenicity, not a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.885 (damaging). BayesDel: 0.512. SpliceAI max delta 0.05 (no splice alteration
- but does not indicate benign effect). All in silico evidence points toward deleterious effect.
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease. The variant has been reported exclusively in probands with SMAD4-related phenotypes (JPS, JP-HHT). Details ▾Hide ▴
Evidence considered
- Variant found only in probands with JPS or JP-HHT phenotype
- not in cases with an alternative genetic cause.
Sources
BP6 ClinVar classifies this variant as Pathogenic (Variation ID 24830), not Benign or Likely Benign. BP6 requires a reputable source to classify the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Pathogenic (not benign). BP6 not applicable.
Sources
BP7 Variant is a missense change (c.1081C>G, p.Arg361Gly), not a synonymous or intronic variant. BP7 applies to synonymous variants with no predicted splice impact or intronic variants outside the splice site. Not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 criterion restricted to synonymous and deep intronic variants.
Not assessed · 4 · no assessment recorded
PS1 No alternative nucleotide change at c.1081 yielding the same amino acid substitution (p.Arg361Gly) has been identified in the literature or variant databases. PS1 requires a different nucleotide change at the same position producing the same amino acid change, already established as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide substitution producing p.Arg361Gly identified.
Still missing
- No c.1081C>A or c.1081C>T variant producing p.Arg361Gly reported.
PP1 Limited cosegregation data are available. The variant occurred as a de novo event in a single proband (Family 230, PMID:15031030) with no additional affected family members to evaluate cosegregation. No multi-generation pedigree with segregation analysis has been published for this variant. Details ▾Hide ▴
Evidence considered
- De novo variant in Family 230
- no additional affected relatives to assess segregation.
Still missing
- No multi-generation family with variant-positive affected and variant-negative unaffected members reported.
Sources
PP2 HCI prior scores are not available for SMAD4 (gene not supported by the HCI prior database). PP2 requires demonstration that missense variants are a common mechanism of disease in a gene with a low rate of benign missense variation, typically assessed via the HCI prior or gene-level Z-score. Without HCI prior data, this criterion cannot be formally applied. Details ▾Hide ▴
Evidence considered
- HCI prior: gene_not_supported. No gene-level missense constraint metric available for SMAD4.
Still missing
- HCI prior data unavailable
- no alternative gene-level missense constraint metric (e.g.
- missense Z-score) applied.
PP5 ClinVar classifies this variant as Pathogenic (Variation ID 24830; 2 clinical laboratories, criteria provided, single submitter). However, PP5 is intended for cases where a reputable source has reported the variant as pathogenic but the evaluating laboratory lacks access to the underlying evidence. In this assessment, all available evidence has been independently evaluated at the criteria level, making PP5 redundant. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 24830: Pathogenic
- 2 clinical laboratories (SCV000756844 Labcorp/Invitae
- SCV002768027 VCGS).
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant is a missense substitution (c.1081C>G, p.Arg361Gly) and does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice site). Per ClinGen SVI PVS1 recommendations (PMC6185798), the generic PVS1 framework is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant type eligible for PVS1 under generic framework.
Sources
PM5 N/APM5 candidate harvesting could not confirm classic same-residue comparator variants suitable for PM5 application. While c.1081C>A (p.Arg361Ser) exists at the same residue, it has not been established as pathogenic through functional or clinical evidence (PMID:22316667 demonstrated only 8% reduction in BMP signaling, not statistically significant). The pm5_candidates pipeline also returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- c.1081C>A (p.Arg361Ser) is the only known alternative substitution at residue 361 but lacks established pathogenicity.
Still missing
- No pathogenic comparator variant at residue 361 with a different amino acid change.
Sources
pm5_candidatesPMID:22316667 ↗
PM6 N/AThe confirmed de novo event has been applied at the strong level under PS2 (paternity and maternity confirmed by haplotype analysis, PMID:15031030). PM6 (assumed de novo without confirmed parentage) addresses a lower evidence tier that has been superseded by the confirmed de novo observation. No additional unconfirmed de novo reports exist for this variant. Details ▾Hide ▴
Evidence considered
- De novo event already captured under PS2 at strong level with confirmed parentage.
Sources
BP3 N/AVariant is a missense substitution; BP3 applies to in-frame deletions or insertions in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 (different nucleotide change at the same position resulting in a different amino acid change, known to be pathogenic) is not a criterion in the ACMG/AMP 2015 standard framework and does not appear in the generic ACMG classification rules used for this case. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SMAD4
- Transcript
- NM_005359.5
- Coding (HGVS c.)
- NM_005359.5:c.1081C>G
- Protein (HGVS p.)
- NP_005350.1:p.(Arg361Gly)
- GRCh38
- chr18:51065548 C>G
- GRCh37
- chr18:48591918 C>G
- ClinVar
- 24830
- COSMIC
- COSV61686083
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 v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.885
- BayesDel
- 0.512
How the predictions were used
PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score 0.885 (strongly damaging, well above 0.75 threshold). The variant lies within the highly conserved MH2 domain at a residue within a statistically significant mutational hotspot. SpliceAI predicts no cryptic splice impact (max delta 0.05), consistent with a pure missense mechanism. BayesDel score 0.512 provides additional, though weaker, supporting evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.885 (damaging). BayesDel: 0.512. SpliceAI max delta: 0.05 (no splice impact
- consistent with missense mechanism). Residue in statistically significant hotspot within conserved MH2 domain.
Sources
BP4 Multiple in silico tools predict a deleterious effect. REVEL score 0.885 is strongly in the damaging range (>0.75). SpliceAI predicts no splice impact (max delta 0.05), which is consistent with a missense mechanism rather than a benign indication. Computational evidence supports pathogenicity, not a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.885 (damaging). BayesDel: 0.512. SpliceAI max delta 0.05 (no splice alteration
- but does not indicate benign effect). All in silico evidence points toward deleterious effect.
Sources
BP7 Variant is a missense change (c.1081C>G, p.Arg361Gly), not a synonymous or intronic variant. BP7 applies to synonymous variants with no predicted splice impact or intronic variants outside the splice site. Not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 criterion restricted to synonymous and deep intronic variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.885. BayesDel score = 0.512189.
8 paper records listed. 2 cited in the classification.
Cited in the classification
-
PMID 15031030 ↗A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).Gallione CJ et al. · 2004 Mar 13c.1081C>G (R361G) identified as a de novo mutation in the proband of Family 230 with juvenile polyposis and hereditary hemorrhagic telangiectasia overlap syndrome. The proband presented with colonic juvenile polyps, anemia, telangiectases, and epistaxis. Mutation was absent from both unaffected parents and chromosome 18 haplotypes confirmed biological parentage. Mutation cosegregated with the JP-HHT phenotype where multiple affected family members were available.→ PS2 → PS4 → PP4 Names this variant
Source detail
The third de-novo mutation was found in family 230; the mutation (1081C→G, R361G) was seen only in the proband who has many colonic polyps and both telangiectases and epistaxis. The mutation was not found in either unaffected parent.
Location Table 1 (line 814); Results text (lines 912-916); Figure (Family 230 pedigree, lines 420-421)
Context Clinical ascertainment, Sanger sequencing of MADH4 coding exons, chromosome 18 haplotype analysis for parentage confirmation
-
PMID 18823382 ↗The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis.Calva-Cerqueira D et al. · 2009 Janc.1081C>G (R361G) listed in Table 1 among SMAD4 mutations identified by direct sequencing in 102 juvenile polyposis probands. Proband JP71 carried this variant as a sporadic case with one affected family member. The variant falls within MRR1 (Mutational Rich Region 1), the most frequently mutated region of SMAD4 (25% of all reported mutations located in codons 330-370 of the MH2 domain).→ PS4 → PM1 Names this variant
Source detail
1081C.G / R361G
Location Table 1 (lines 231-233); Discussion (lines 366-388)
Context Direct Sanger sequencing of SMAD4 coding exons and intron-exon boundaries in 102 JPS probands
Other recorded publications
-
PMID 22316667 ↗Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling.The paper reports that two patients in the JP database shared substitutions at nucleotide 1081 of SMAD4. Eleven SMAD4 mutations were functionally assessed in a BMP-responsive luciferase reporter assay. However, the specific substitution tested at position 1081 was c.1081C>A (R361S), not c.1081C>G (R361G). R361S showed an 8% reduction in BMP signaling that was not statistically significant.Names this variant
Quoted passage
two others shared substitutions of nucleotide 1081
Results section (two others shared substitutions of nucleotide 1081; 1081C>A R361S listed among four missense mutations tested); Figure 1
-
PMID 25523272 ↗Intratumoral heterogeneity in a minority of ovarian low-grade serous carcinomas.SMAD4 R361G (chr18:48,591,918C>G) detected as a somatic mutation in ovarian low-grade serous carcinoma (case LGSC-12). The mutation was stable across all 6 tumor samples from primary and recurrent sites with an allelic fraction of 31-55%, suggesting a clonal driver event. This is a somatic, not germline, observation in a distinct tumor type.Names this variant
Quoted passage
Sequencing of 4 primary LGSC samples and 2 recurrent LGSC samples revealed somatic non-synonymous mutations in both BRAF (chr7:140,453,136A>T, V600E) and SMAD4 (chr18:48,591,918C>G, R361G).
Abstract; Results section paragraph on LGSC-12; Table 2; Figure 1
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PMID 10751092 ↗Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).Consensus clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (Curaçao criteria). The paper predates the identification of SMAD4 as an HHT/JP gene and does not discuss any specific SMAD4 variants.Does not name this variant
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PMID 15235019 ↗The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.Howe JR et al. · 2004The prevalence of SMAD4 and BMPR1A mutations in juvenile polyposis was determined by sequencing in a cohort of JP probands. NM_005359.5:c.1081C>G was not identified in this paper.Does not name this variant
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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 the interpretation of sequence variants. This is a methodology paper that defines the classification framework and does not discuss any specific SMAD4 variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
2 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/24830/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-48591918-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-51065548-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/18-51065548-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005359.5%3Ac.1081…
- OncoKB ↗www.oncokb.org/gene/SMAD4/R361G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128486132
- 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 v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 24830)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.885. BayesDel score = 0.512189.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely 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; COSV61686083, n = 15 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.