Variant summary: SMAD4 c.1573A>G (p.Ile525Val) results in a conservative amino acid change located in the SMAD domain, Dwarfin-type (IPR001132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 254026 control chromosomes, predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 490 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 Latino origin. c.1573A>G has been reported in the literature in both non-cancer controls (example, Johnston_2012, Tram_2011) as well as in 2 patients with gastrointestinal polyposis (example, Ngeow_2013) and in others with cancer phenotypes and phenotypes not specified (example, Yorczyk_2015, Yurgelun_2015, Ring_2016, Maxwell_2016, Pelusi_2019, Tung_2015). The variant was also reported in somatic cancer tissues (example, Li_2015, Siroy_2015, Hamblin_2017). These report(s) 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. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The predominant consensus among all submitters is benign/likely benign (n=13). Based on the evidence outlined above and in alignment with the predominant consensus, the variant was classified as benign.
ClinVar Genomic variation as it relates to human health
NM_005359.6(SMAD4):c.1573A>G (p.Ile525Val)
Germline
Classification
Help
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.
(29)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(7); Likely benign(11)
Uncertain significance(2); Benign(7); Likely benign(11)
29
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005359.6(SMAD4):c.1573A>G (p.Ile525Val)
Variation ID: 41788 Accession: VCV000041788.65
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q21.2 18: 51078381 (GRCh38) [ NCBI UCSC ] 18: 48604751 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 12, 2013 Oct 20, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005359.6:c.1573A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005350.1:p.Ile525Val missense NC_000018.10:g.51078381A>G NC_000018.9:g.48604751A>G NG_013013.2:g.115342A>G LRG_318:g.115342A>G LRG_318t1:c.1573A>G LRG_318p1:p.Ile525Val - Protein change
- I525V
- Other names
-
p.I525V:ATT>GTT
- Canonical SPDI
- NC_000018.10:51078380:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00071
Trans-Omics for Precision Medicine (TOPMed) 0.00073
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00085
The Genome Aggregation Database (gnomAD), exomes 0.00058
Exome Aggregation Consortium (ExAC) 0.00070
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SMAD4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2160 | 2202 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (12) |
criteria provided, multiple submitters, no conflicts
|
May 10, 2023 | RCV000034710.44 | |
| Likely benign (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148889.11 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 28, 2019 | RCV000123259.27 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000327173.16 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 15, 2023 | RCV000213006.26 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 28, 2020 | RCV000771070.10 | |
| Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 10, 2023 | RCV000383039.18 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 15, 2021 | RCV001170612.11 | |
| Benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV001420980.15 | |
| Benign (1) |
criteria provided, single submitter
|
Nov 6, 2018 | RCV002310997.9 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Feb 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918227.2
First in ClinVar: Jun 02, 2019 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SMAD4 c.1573A>G (p.Ile525Val) results in a conservative amino acid change located in the SMAD domain, Dwarfin-type (IPR001132) of the encoded protein sequence. Three … (more)
Variant summary: SMAD4 c.1573A>G (p.Ile525Val) results in a conservative amino acid change located in the SMAD domain, Dwarfin-type (IPR001132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 254026 control chromosomes, predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 490 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 Latino origin. c.1573A>G has been reported in the literature in both non-cancer controls (example, Johnston_2012, Tram_2011) as well as in 2 patients with gastrointestinal polyposis (example, Ngeow_2013) and in others with cancer phenotypes and phenotypes not specified (example, Yorczyk_2015, Yurgelun_2015, Ring_2016, Maxwell_2016, Pelusi_2019, Tung_2015). The variant was also reported in somatic cancer tissues (example, Li_2015, Siroy_2015, Hamblin_2017). These report(s) 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. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The predominant consensus among all submitters is benign/likely benign (n=13). Based on the evidence outlined above and in alignment with the predominant consensus, the variant was classified as benign. (less)
|
|
|
Likely benign
(Jan 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333201.2
First in ClinVar: May 31, 2020 Last updated: Jan 01, 2022 |
|
|
|
Benign
(Nov 28, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002538308.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Likely benign
(Oct 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149791.14
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25637381, 23399955, 25742471, 26919633, 21835029, 27153395, 30719162, 25695693, 25314059, 25318351, 22703879, 25980754, 25356985, 25589618, 27443514, 28196074, … (more)
This variant is associated with the following publications: (PMID: 25637381, 23399955, 25742471, 26919633, 21835029, 27153395, 30719162, 25695693, 25314059, 25318351, 22703879, 25980754, 25356985, 25589618, 27443514, 28196074, 28451460) (less)
|
|
|
Benign
(Mar 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902594.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140895.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely benign
(Jan 01, 2018)
|
criteria provided, single submitter
Method: research
|
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001439414.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
Comment:
BS1 +BP2
Number of individuals with the variant: 1
|
|
|
Likely benign
(Nov 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002067453.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
|
Likely benign
(Apr 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605222.5
First in ClinVar: Sep 28, 2017 Last updated: Mar 04, 2023 |
|
|
|
Uncertain significance
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004026943.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166566.14
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Jan 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000784868.2
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
|
|
|
Likely benign
(Aug 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806695.1
First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000409103.3
First in ClinVar: Dec 06, 2016 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Myhre syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000409104.3
First in ClinVar: Dec 06, 2016 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000409102.3
First in ClinVar: Dec 06, 2016 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004017788.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally … (more)
This variant is considered likely benign. 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)
|
|
|
Likely benign
(May 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889845.4
First in ClinVar: Feb 17, 2019 Last updated: Jan 06, 2024 |
|
|
|
Benign
(Nov 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Familial thoracic aortic aneurysm and aortic dissection
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000187245.9
First in ClinVar: Aug 06, 2014 Last updated: Jun 09, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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)
|
|
|
Benign
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585684.15
First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024 |
Comment:
SMAD4: PP2, BS1, BS2
Number of individuals with the variant: 1
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930102.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Likely benign
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Gastrointestinal polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190634.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919862.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
variant of unknown significance
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043501.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 2
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
|
|
|
Benign
(May 24, 2019)
|
no assertion criteria provided
Method: research
|
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Affected status: no
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV001446374.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020
Comment:
Individuals in one family that had colon polyps did not have this variant. This variant has been reported at a frequency of 1 in 900 … (more)
Individuals in one family that had colon polyps did not have this variant. This variant has been reported at a frequency of 1 in 900 individuals (gnomad.broadinstitute.org). Variants present at this population frequency are unlikely to be associated with high penetrance hereditary cancer risk. Computer software programs predict that this variant does not impact protein function. The observation that this variant does not segregate with colon polyps in your family adds more evidence that it is benign. This variant has been classified as likely benign or benign by other clinical laboratories. Bayesian analysis integrating all of this data (PMID: 29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of benign. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study. (less)
|
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808810.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001951781.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Likely benign
(-)
|
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: SCV001964560.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035606.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
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Comment:
Comment:
This variant is associated with the following publications: (PMID: 25637381, 23399955, 25742471, 26919633, 21835029, 27153395, 30719162, 25695693, 25314059, 25318351, 22703879, 25980754, 25356985, 25589618, 27443514, 28196074, 28451460)
Comment:
BS1 +BP2
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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is considered likely benign. 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.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Comment:
SMAD4: PP2, BS1, BS2
Comment:
Converted during submission to Uncertain significance.
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. |
Comment:
Variant summary: SMAD4 c.1573A>G (p.Ile525Val) results in a conservative amino acid change located in the SMAD domain, Dwarfin-type (IPR001132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 254026 control chromosomes, predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 490 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 Latino origin. c.1573A>G has been reported in the literature in both non-cancer controls (example, Johnston_2012, Tram_2011) as well as in 2 patients with gastrointestinal polyposis (example, Ngeow_2013) and in others with cancer phenotypes and phenotypes not specified (example, Yorczyk_2015, Yurgelun_2015, Ring_2016, Maxwell_2016, Pelusi_2019, Tung_2015). The variant was also reported in somatic cancer tissues (example, Li_2015, Siroy_2015, Hamblin_2017). These report(s) 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. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The predominant consensus among all submitters is benign/likely benign (n=13). Based on the evidence outlined above and in alignment with the predominant consensus, the variant was classified as benign.
Comment:
This variant is associated with the following publications: (PMID: 25637381, 23399955, 25742471, 26919633, 21835029, 27153395, 30719162, 25695693, 25314059, 25318351, 22703879, 25980754, 25356985, 25589618, 27443514, 28196074, 28451460)
Comment:
BS1 +BP2
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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is considered likely benign. 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.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Comment:
SMAD4: PP2, BS1, BS2
Comment:
Converted during submission to Uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. | Shovlin CL | Blood | 2020 | PMID: 32573726 |
| Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. | Pelusi S | Scientific reports | 2019 | PMID: 30842500 |
| Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service. | Hamblin A | PLoS medicine | 2017 | PMID: 28196074 |
| Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Genomic analysis of metastatic cutaneous squamous cell carcinoma. | Li YY | Clinical cancer research : an official journal of the American Association for Cancer Research | 2015 | PMID: 25589618 |
| Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
| 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 |
| Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. | Siroy AE | The Journal of investigative dermatology | 2015 | PMID: 25148578 |
| Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. | Ngeow J | Gastroenterology | 2013 | PMID: 23399955 |
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
| 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 |
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Text-mined citations for rs149755320 ...
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Record last updated Nov 03, 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.