SMAD4 c.1081C>A, p.(Arg361Ser)

26 criteria with recorded statuses: 6 met · 6 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 is not applicable to missense variants. This variant (c.1081C>A, p.Arg361Ser) is a missense substitution in exon 9 of SMAD4 and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴

Evidence considered

• Variant is a missense substitution
• not a null variant eligible for PVS1.

Sources

pvs1_generic_framework ↗

BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. SMAD4 has numerous well-documented pathogenic missense mutations (including at codon 361) that cause JPS, HHT, and JP-HHT syndrome. Therefore BP1 is not applicable. Details ▾Hide ▴

Evidence considered

• SMAD4 missense variants are a well-established cause of JPS and JP-HHT.

Sources

PMID:11583957 ↗PMID:17873119 ↗PMID:20101697 ↗

BP2 N/ABP2 applies to observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder. No such data are available for this variant; however, SMAD4-related disorders are autosomal dominant with haploinsufficiency as the mechanism, so observation in trans is not expected. Details ▾Hide ▴

Evidence considered

• SMAD4-associated JPS/HHT are autosomal dominant loss-of-function disorders.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_005359.5:c.1081C>A is a missense variant (p.Arg361Ser), not synonymous. Details ▾Hide ▴

Evidence considered

• Variant is missense (c.1081C>A
• p.Arg361Ser)
• not synonymous.

PS5 N/APS5 requires the same nucleotide change to have been previously established as pathogenic. No independently established pathogenic variant at c.1081C>A exists; the single ClinVar submission for this variant (Likely pathogenic, single submitter) does not constitute independent establishment. Details ▾Hide ▴

Evidence considered

• ClinVar VariationID 24822 has only one submitter
• insufficient for PS5 which requires independent confirmation.

Sources

clinvar ↗

Identifiers

Gene

SMAD4

Transcript

NM_005359.5

Coding (HGVS c.)

NM_005359.5:c.1081C>A

Protein (HGVS p.)

NP_005350.1:p.(Arg361Ser)

GRCh38

chr18:51065548 C>A

GRCh37

chr18:48591918 C>A

ClinVar

24822

COSMIC

COSV61685418

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.

Statements

SpliceAI and Pangolin

Other predictors

REVEL

0.912

BayesDel

0.534

How the predictions were used

PP3 SupportingMultiple in silico prediction tools support a deleterious effect: REVEL score 0.912 (threshold >0.7), BayesDel score 0.534 (threshold >0.5). SpliceAI predicts no significant splicing impact (max delta = 0.14). The combined in silico evidence supports a damaging effect on protein function. Details ▾Hide ▴

Evidence considered

• REVEL score: 0.912 (deleterious).
• BayesDel score: 0.534 (deleterious).
• SpliceAI max delta: 0.14 (no significant splicing impact
• consistent with a missense mechanism).

Sources

revelbayesdelspliceai ↗

BP4 BP4 requires multiple in silico tools to predict no impact on the gene product. In contrast, REVEL (0.912) and BayesDel (0.534) both predict a deleterious effect. SpliceAI shows no significant splicing impact (max delta 0.14), but this alone is insufficient to meet BP4 when protein-level predictors are strongly damaging. Details ▾Hide ▴

Evidence considered

• REVEL 0.912: damaging.
• BayesDel 0.534: damaging.
• SpliceAI max delta 0.14: no splicing impact
• but does not override damaging protein predictions.

Sources

revelbayesdelspliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_005359.5:c.1081C>A is a missense variant (p.Arg361Ser), not synonymous. Details ▾Hide ▴

Evidence considered

• Variant is missense (c.1081C>A
• p.Arg361Ser)
• not synonymous.

Statement

9 paper records listed. 5 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

• Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers.

  Woodford-Richens KL et al. · 2001 Oct

  Comprehensive analysis of germline SMAD4 mutations in JPS. Reports family AC/AF with a p.Arg361Cys (c.1081C>T) missense mutation, which leads to loss of SMAD4 protein expression in polyps by immunohistochemistry. The specific variant c.1081C>A (p.Arg361Ser) was not identified. Demonstrates that SMAD4 missense mutations at codon 361 are pathogenic and result in protein instability.

  → PM1 → PM5 → PP2 Does not name this variant
  PMID 11583957 ↗
  Source detail

  Our patient with a germline missense mutation carried an R361C change. This mutation maps to the loop/helix domain in the C-terminal of SMAD4 and has also been found in a sporadic colorectal.

  Location Table 2 (family AC/AF: c→t 1083 R361C); Discussion (reference 15: Shi 1997 functional characterization of R361C)

• SMAD4 mutations found in unselected HHT patients.

  Gallione CJ et al. · 2006 Oct

  Identifies SMAD4 mutations in unselected HHT patients without prior JP diagnosis. Reports c.1081C>T (p.Arg361Cys) in two unrelated HHT patients (5068, 3892) who were subsequently found to have colonic polyps. The specific variant c.1081C>A (p.Arg361Ser) was not identified. Demonstrates that SMAD4 codon 361 missense mutations cause JP-HHT syndrome.

  → PM1 → PM5 Does not name this variant
  PMID 16613914 ↗
  Source detail

  A missense mutation in exon 8 of SMAD4, c.1081C→T, R361C, was found. ... Individual 3892 ... harboured the same SMAD4 exon 8 missense mutation (c.1081C→T, R361C).

  Location Results section; Table 1; Figure 1

• High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.

  Aretz S et al. · 2007 Nov

  Reports mutation and genotype-phenotype analysis in 80 unrelated JPS families. Identifies multiple pathogenic missense changes at SMAD4 codon 361: c.1081C>T (p.Arg361Cys) in patient JUV-87, and c.1082G>A (p.Arg361His) as a de novo mosaic in patient JUV-81. The specific variant c.1081C>A (p.Arg361Ser) was not identified. Establishes a strong genotype-phenotype correlation for gastric polyposis in SMAD4 mutation carriers.

  → PM1 → PM5 → PP2 Does not name this variant
  PMID 17873119 ↗
  Source detail

  Two of the four missense mutations (patients JUV-14 and JUV-78) were proven to have occurred de novo. In a third patient (JUV-81), only a faint mutant signal (c.1082G→A;p.Arg361His) was found during sequencing of exon 8, suggesting that this mutation was present as a mosaic.

  Location Table 2 (patients JUV-81 and JUV-87); Results section

• Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

  Gallione C et al. · 2010 Feb

  Characterizes the overlapping spectra of SMAD4 mutations in JP and JP-HHT. Reports three different pathogenic missense changes at codon 361: c.1081C>T (p.Arg361Cys) in two JP-HHT patients, c.1082G>T (p.Arg361Leu), and c.1082G>A (p.Arg361His). The specific variant c.1081C>A (p.Arg361Ser) was not identified. Concludes that any SMAD4 mutation can cause JP-HHT and that codon 361 is a recurrent site of pathogenic missense variation.

  → PM1 → PM5 → PP2 Does not name this variant
  PMID 20101697 ↗
  Source detail

  Two additional protein-truncating mutations were also identified in exon 2 (MH1 domain) and exon 5 (Linker region). Ten patients harbored missense mutations in exons 8, 9, or 11 encoding the MH2 domain of the protein.

  Location Table I (patients 3760, 4138: c.1081C>T p.R361C; 3953: c.1082G>T p.R361L; 4116: c.1082G>A p.R361H); Results section

• Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.

  Houlston R et al. · 1998 Nov

  Reports a germline missense mutation in SMAD4 at codon 361, specifically c.1081C>T (CGC→TGC, p.Arg361Cys) in a familial JPS patient (AF). This is a different nucleotide and amino acid substitution from c.1081C>A (p.Arg361Ser). The paper demonstrates that germline SMAD4 missense mutations cause JPS and that only a minority of JPS cases are attributable to SMAD4.

  → PM1 → PM5 Does not name this variant
  PMID 9811934 ↗
  Source detail

  Sequencing (Fig. 2) showed this to result from a missense mutation in codon 361 of DPC4 (CGC→TGC, Arg→Cys).

  Location Results (page 1909-1910); Figure 2

Other recorded publications

• The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.

  Howe JR et al. · 2004

  Determines the prevalence of SMAD4 (MADH4) and BMPR1A mutations in juvenile polyposis. The specific variant NM_005359.5:c.1081C>A (p.Arg361Ser) was not identified in this paper. The paper documents the spectrum of SMAD4 mutations in JPS but does not discuss codon 361 variants.

  Does not name this variant
  PMID 15235019 ↗
• A structural basis for mutational inactivation of the tumour suppressor Smad4.

  Shi Y et al. · 1997

  Provides the structural basis for mutational inactivation of SMAD4. Characterizes the functional impact of SMAD4 missense mutations including R361C on hetero- and homo-oligomerization. The specific variant p.Arg361Ser is not studied. Confirms that codon 361 is critical for SMAD4 MH2 domain function.

  Does not name this variant
  PMID 9214508 ↗
• Analysis of genetic and phenotypic heterogeneity in juvenile polyposis.

  Woodford-Richens K et al. · 2000

  Analyzes genetic and phenotypic heterogeneity in JPS including SMAD4 mutation screening. The specific variant NM_005359.5:c.1081C>A (p.Arg361Ser) was not identified in this paper. The study contributes to establishing SMAD4 as a JPS gene with a spectrum of mutations.

  Does not name this variant
  PMID 10764709 ↗
• Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

  Describes the Sherloc refinement of ACMG-AMP variant classification criteria. This is a methodological paper that does not discuss SMAD4 variants or report any patient data. The specific variant NM_005359.5:c.1081C>A is not mentioned.

  Does not name this variant
  PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

• ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/24822/
• gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-48591918-C-A?dataset=gnomad_r2_1
• gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-51065548-C-A?dataset=gn…
• gnomAD-Canada ↗http://192.168.4.76:8001/variant/18-51065548-C-A
• SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005359.5%3Ac.1081…
• OncoKB ↗www.oncokb.org/gene/SMAD4/R361S
• COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128485472
• Cancer hotspots ↗www.cancerhotspots.org/

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.