ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.20C>T (p.Thr7Met)
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(12); Benign(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005359.6(SMAD4):c.20C>T (p.Thr7Met)
Variation ID: 183733 Accession: VCV000183733.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 51047066 (GRCh38) [ NCBI UCSC ] 18: 48573436 (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 Jan 6, 2017 May 12, 2024 Mar 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005359.6:c.20C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005350.1:p.Thr7Met missense NC_000018.10:g.51047066C>T NC_000018.9:g.48573436C>T NG_013013.2:g.84027C>T LRG_318:g.84027C>T LRG_318t1:c.20C>T LRG_318p1:p.Thr7Met - Protein change
- T7M
- Other names
- -
- Canonical SPDI
- NC_000018.10:51047065:C:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00031
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
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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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2023 | RCV000162438.20 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV000196213.23 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 28, 2023 | RCV000589285.23 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764159.10 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV001123230.15 | |
Benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001123231.12 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 26, 2022 | RCV002285148.8 | |
Benign (1) |
criteria provided, single submitter
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Dec 7, 2021 | RCV002310723.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV001328507.12 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 19, 2024 | RCV002468936.9 | |
SMAD4-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 25, 2023 | RCV003398830.4 |
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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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Uncertain significance
(Apr 27, 2017)
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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: SCV001282047.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Apr 27, 2017)
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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: SCV001282048.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(Apr 27, 2017)
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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: SCV001283269.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Sep 06, 2021)
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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: SCV002538316.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The SMAD4 c.20C>T (p.T7M) variant has been reported in at least 2 individuals with colon cancer (PMIDs 25559809, 29684080). This variant was observed in 3/25100 … (more)
The SMAD4 c.20C>T (p.T7M) variant has been reported in at least 2 individuals with colon cancer (PMIDs 25559809, 29684080). This variant was observed in 3/25100 chromosomes in the European Finnish subpopulation according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 183733). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Nov 08, 2016)
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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: SCV000489675.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(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: SCV004017808.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Jun 28, 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: SCV000293338.13
First in ClinVar: Jul 24, 2016 Last updated: Nov 25, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26343384, 25559809, 28873162, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26343384, 25559809, 28873162, 29684080) (less)
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Uncertain significance
(May 09, 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: SCV002048437.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
Comment:
The SMAD4 c.20C>T; p.Thr7Met variant (rs372316981), is reported in the literature in an individual with colorectal cancer (Chubb 2015). This variant is reported in ClinVar … (more)
The SMAD4 c.20C>T; p.Thr7Met variant (rs372316981), is reported in the literature in an individual with colorectal cancer (Chubb 2015). This variant is reported in ClinVar (Variation ID: 183733) and is found in the general population with an overall allele frequency of 0.005% (15/282646 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.439). However, due to limited information, the clinical significance of the p.Thr7Met variant is uncertain at this time. References: Chubb D et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J Clin Oncol. 2015 Feb 10;33(5):426-32. PMID: 25559809. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Myhre syndrome
Juvenile polyposis syndrome Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Carcinoma of pancreas
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895161.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely benign
(Sep 17, 2020)
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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: SCV002046218.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Benign
(Dec 07, 2021)
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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: SCV000212786.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more)
This alteration is classified as 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
(Jan 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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SMAD4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105918.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SMAD4 c.20C>T variant is predicted to result in the amino acid substitution p.Thr7Met. This variant has been detected in at least one individual with … (more)
The SMAD4 c.20C>T variant is predicted to result in the amino acid substitution p.Thr7Met. This variant has been detected in at least one individual with a personal or family history of colon cancer (Chubb et al. 2015. PubMed ID: 25559809, Table A1). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-48573436-C-T). In ClinVar, this variant has conflicting interpretations, ranging from uncertain to benign (https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/clinvar/variation/183733/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Apr 10, 2023)
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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: SCV000686533.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 7 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with methionine at codon 7 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 29684080). This variant has been identified in 15/282646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 26, 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: SCV000254841.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 7 of the SMAD4 protein (p.Thr7Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 7 of the SMAD4 protein (p.Thr7Met). This variant is present in population databases (rs372316981, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of colon cancer (PMID: 25559809, 29684080). ClinVar contains an entry for this variant (Variation ID: 183733). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004819995.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces threonine with methionine at codon 7 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with methionine at codon 7 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 29684080). This variant has been identified in 15/282646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 9
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Likely benign
(Mar 19, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698573.3
First in ClinVar: Mar 17, 2018 Last updated: May 12, 2024 |
Comment:
Variant summary: SMAD4 c.20C>T (p.Thr7Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SMAD4 c.20C>T (p.Thr7Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 1613528 control chromosomes. The observed variant frequency is approximately 2.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Colon Cancer phenotype (2.3e-05), strongly suggesting that the variant is benign. c.20C>T has been reported in the literature in at-least one individual affected with Colon Cancer (Chubb_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Colon and/or SMAD4-related Cancer. At-least one database (LOVD) publishes this variant as co-occuring with another variant 1244_1247delACAG in the SMAD4 gene. This co-occuring variant is annotated as SMAD4, c.1245_1248delCAGA (p.Asp415Glufs), a pathogenic variant in the ClinVar database. This provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 183733). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Sep 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Pulmonary arterial hypertension
Affected status: unknown
Allele origin:
germline
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John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine
Accession: SCV002575052.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
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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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Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. | Chubb D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25559809 |
Text-mined citations for rs372316981 ...
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.