ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.424+5G>A
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(6); Benign(2); Likely benign(10)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005359.6(SMAD4):c.424+5G>A
Variation ID: 127950 Accession: VCV000127950.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 51048865 (GRCh38) [ NCBI UCSC ] 18: 48575235 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005359.6:c.424+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000018.10:g.51048865G>A NC_000018.9:g.48575235G>A NG_013013.2:g.85826G>A LRG_318:g.85826G>A LRG_318t1:c.424+5G>A - Protein change
- Other names
- IVS3+5G>A
- Canonical SPDI
- NC_000018.10:51048864:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00013
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00022
Exome Aggregation Consortium (ExAC) 0.00023
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SMAD4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2075 | 2117 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 17, 2020 | RCV000115883.24 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 23, 2018 | RCV000204731.22 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 10, 2023 | RCV000306889.15 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000346296.13 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV000656977.28 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 25, 2016 | RCV000770696.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV000213004.30 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV002228348.13 | |
Likely benign (1) |
criteria provided, single submitter
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May 24, 2019 | RCV002311002.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(May 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786540.2
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Uncertain significance
(Jan 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157713.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022 |
Comment:
The SMAD4 c.424+5G>A variant (rs200772603) is reported in the literature in an individual with suspected Lynch syndrome (Yurgelun 2015) and another individual referred for hereditary … (more)
The SMAD4 c.424+5G>A variant (rs200772603) is reported in the literature in an individual with suspected Lynch syndrome (Yurgelun 2015) and another individual referred for hereditary cancer testing (Tsaousis 2019). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (47/128762 alleles) in the Genome Aggregation Database. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.424+5G>A variant is uncertain at this time. References: Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. (less)
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Likely benign
(Aug 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002068341.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(May 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186740.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551307.5
First in ClinVar: Jul 30, 2022 Last updated: Feb 14, 2024 |
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822202.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Nov 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000902173.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Likely benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000409088.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myhre syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000409087.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000409089.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely benign
(Apr 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918223.2
First in ClinVar: Jun 02, 2019 Last updated: Apr 29, 2021 |
Comment:
Variant summary: SMAD4 c.424+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: SMAD4 c.424+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00022 in 250792 control chromosomes, predominantly at a frequency of 0.00038 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 190 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.424+5G>A has been reported in the literature in individuals affected with cancer including colorectal cancer, hereditary breast and ovarian cancer, pancreatic ductal adenocarcinoma and familial intestinal gastric cancer (e.g. Tung_2015, Yurgelun_2015, Mandelker_2017, Chaffee_2018, Schubert_2019, Tsaousis_2019, Carvalho_2021). These reports do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and seven ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Nov 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000686539.4
First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021 |
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Likely benign
(Nov 12, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002538323.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149792.19
First in ClinVar: May 17, 2014 Last updated: May 13, 2023 |
Comment:
Observed in individuals with Lynch syndrome-associated cancer, familial gastric cancer, pancreatic cancer, breast cancer, or polyps (Tung et al., 2015; Yurgelun et al., 2015; Jelsig … (more)
Observed in individuals with Lynch syndrome-associated cancer, familial gastric cancer, pancreatic cancer, breast cancer, or polyps (Tung et al., 2015; Yurgelun et al., 2015; Jelsig et al., 2016; Chaffee et al., 2018; Schubert et al., 2019; Carvalho et al., 2021), but has not been published in individuals with connective tissue disorders to our knowledge; In silico analysis supports that this variant does not alter splicing; however, published functional studies demonstrate evidence of aberrant splicing (Shiraishi et al., 2021); This variant is associated with the following publications: (PMID: 32066632, 25980754, 28873162, 31159747, 27146957, Shiraishi2021, 25186627, 28726808, 30426508) (less)
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Likely benign
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004017793.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or … (more)
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. (less)
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Benign
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602194.3
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00037 (47/128762 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.00037 (47/128762 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 31159747 (2019), 30426508 (2018), and 25186627 (2015)), pancreatic cancer (PMID: 28726808 (2018)), gastric cancer (PMID: 32066632 (2021)), colon cancer (PMID: 25980754 (2015)), and hamartomatous polyposis syndrome (PMID: 2714957 (2016)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper SMAD4 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259352.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
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Likely benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004701678.3
First in ClinVar: Mar 10, 2024 Last updated: May 12, 2024 |
Comment:
SMAD4: BP4, BS1
Number of individuals with the variant: 3
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966476.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956576.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives. | Carvalho J | Journal of medical genetics | 2021 | PMID: 32066632 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. | Schubert S | International journal of cancer | 2019 | PMID: 30426508 |
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. | Chaffee KG | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28726808 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps. | Jelsig AM | Scandinavian journal of gastroenterology | 2016 | PMID: 27146957 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Text-mined citations for rs200772603 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.