ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.1086T>C (p.Phe362=)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005359.6(SMAD4):c.1086T>C (p.Phe362=)
Variation ID: 132693 Accession: VCV000132693.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 51065553 (GRCh38) [ NCBI UCSC ] 18: 48591923 (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 Jun 1, 2016 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005359.6:c.1086T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005350.1:p.Phe362= synonymous NC_000018.10:g.51065553T>C NC_000018.9:g.48591923T>C NG_013013.2:g.102514T>C LRG_318:g.102514T>C LRG_318t1:c.1086T>C LRG_318p1:p.Phe362= - Protein change
- Other names
- p.F362F:TTT>TTC
- Canonical SPDI
- NC_000018.10:51065552:T:C
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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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0.00319 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00172
The Genome Aggregation Database (gnomAD), exomes 0.00182
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00208
1000 Genomes Project 0.00319
The Genome Aggregation Database (gnomAD) 0.00228
Trans-Omics for Precision Medicine (TOPMed) 0.00243
1000 Genomes Project 30x 0.00312
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
Help
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 |
2062 | 2104 |
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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Benign (2) |
criteria provided, single submitter
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Mar 17, 2016 | RCV000128172.17 | |
Benign/Likely benign (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000213005.35 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000273483.13 | |
Benign (1) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV000388633.13 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000587945.35 | |
Benign (1) |
criteria provided, single submitter
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Aug 16, 2017 | RCV000770698.10 | |
Benign (2) |
criteria provided, single submitter
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Jan 13, 2018 | RCV001083846.15 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV001507168.15 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 25, 2014 | RCV002310676.8 |
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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Benign
(Feb 23, 2016)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698561.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.1086T>C in SMAD4 gene is a synonymous change that involves a conserved nucleotide. 5/5 programs in Alamut predict that this variant does … (more)
Variant summary: The c.1086T>C in SMAD4 gene is a synonymous change that involves a conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant was found in multiple affected individuals presented with personal and/or family history of cancer. It is present in the control population dataset of ExAC at frequency of 0.17%, including 2 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic SMAD4 variant, suggesting that it is a common polymorphism. However, some of these occurrences may potentially be due to a presence of a processed pseudogene, and, therefore, should be taken with cautions. Lastly, the variant has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken together, this variant has been classified as Benign. (less)
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Benign
(Dec 26, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000171764.11
First in ClinVar: Jun 23, 2014 Last updated: Feb 19, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Dec 14, 2016)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000806688.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Benign
(Aug 16, 2017)
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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: SCV000902175.1 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/hereditary hemorrhagic telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000409100.3
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: SCV000409099.3
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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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: SCV000409101.3
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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Benign
(Mar 17, 2016)
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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
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686513.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015518.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Likely benign
(Aug 15, 2023)
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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: SCV002552026.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
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Benign
(Aug 24, 2022)
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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: SCV000889838.4
First in ClinVar: Feb 17, 2019 Last updated: Jan 06, 2024 |
|
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Benign
(Sep 22, 2023)
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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: SCV000605223.5
First in ClinVar: Jun 01, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 27, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000860202.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Apr 25, 2019)
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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: SCV002067431.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
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Likely benign
(Sep 25, 2014)
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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
|
Ambry Genetics
Accession: SCV000212861.7
First in ClinVar: Mar 24, 2015 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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Benign
(Feb 01, 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
|
Invitae
Accession: SCV000153829.15
First in ClinVar: Jun 03, 2014 Last updated: Feb 14, 2024 |
|
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Likely benign
(Mar 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: SCV002498379.12
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
SMAD4: BP4, BS1
Number of individuals with the variant: 25
|
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Likely benign
(Oct 10, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000788211.1
First in ClinVar: Apr 13, 2018 Last updated: Apr 13, 2018 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808084.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 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: SCV001957519.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692036.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Generalized juvenile polyposis/juvenile polyposis coli
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548643.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The SMAD4 p.Phe362= variant was identified in 2 of 1004 proband chromosomes (frequency: 0.002) from individuals or families with gastric or breast cancer and was … (more)
The SMAD4 p.Phe362= variant was identified in 2 of 1004 proband chromosomes (frequency: 0.002) from individuals or families with gastric or breast cancer and was present in 1 of 1420 control chromosomes (frequency: 0.001) from healthy individuals (Oliveira 2003, Tram 2011). The variant was also identified in dbSNP (ID: rs1801250) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Color and ARUP; and as likely benign by Ambry Genetics and two other submitters), and in LOVD 3.0 (3x as benign or likely benign). The variant was identified in control databases in 502 of 277188 chromosomes (3 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 84 of 24028 chromosomes (freq: 0.003), Other in 28 of 6466 chromosomes (freq: 0.004), Latino in 103 of 34412 chromosomes (freq: 0.003), European in 133 of 126694 chromosomes (freq: 0.001), Ashkenazi Jewish in 149 of 10150 chromosomes (freq: 0.02), and South Asian in 5 of 30782 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian or Finnish populations. The p.Phe362= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920674.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001975360.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors. | Goswami RS | Clinical cancer research : an official journal of the American Association for Cancer Research | 2015 | PMID: 25695693 |
Biomarkers of TGF-β signaling pathway and prognosis of pancreatic cancer. | Javle M | PloS one | 2014 | PMID: 24465802 |
Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR). | Tram E | Breast cancer research : BCR | 2011 | PMID: 21835029 |
E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. | Oliveira C | European journal of cancer (Oxford, England : 1990) | 2004 | PMID: 15288293 |
Two novel polymorphisms, c1086T>C and c1798C>T, in the MADH4/DPC4 gene. | Moore PS | Human mutation | 2000 | PMID: 10790223 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMAD4 | - | - | - | - |
Text-mined citations for rs1801250 ...
HelpRecord last updated Apr 20, 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.