VCV000041788.65 - ClinVar

NM_005359.6(SMAD4):c.1573A>G (p.Ile525Val)

Germline

Classification

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)

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)

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

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

I525V

Other names

p.I525V:ATT>GTT

Canonical SPDI

NC_000018.10:51078380:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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), exomes 0.00058

Exome Aggregation Consortium (ExAC) 0.00070

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

Links

dbSNP: rs149755320 ClinGen: CA211890 VarSome

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
Gene	OMIM	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.
not provided	Benign/Likely benign (12)	criteria provided, multiple submitters, no conflicts	May 10, 2023	RCV000034710.44
Myhre syndrome	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000327173.16
Familial thoracic aortic aneurysm and aortic dissection	Likely benign (1)	criteria provided, single submitter	Jan 15, 2021	RCV001170612.11
Generalized juvenile polyposis/juvenile polyposis coli	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 28, 2019	RCV000123259.27
not specified	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Aug 15, 2023	RCV000213006.26
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Likely benign (4)	criteria provided, multiple submitters, no conflicts	Apr 10, 2023	RCV000383039.18
Familial thoracic aortic aneurysm and aortic dissection Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	Nov 6, 2018	RCV002310997.9
Gastrointestinal polyposis	Likely benign (1)	no assertion criteria provided	Jun 1, 2014	RCV000148889.11
Hereditary cancer-predisposing syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 28, 2020	RCV000771070.10
Juvenile polyposis syndrome	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001420980.15

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.
Likely benign (Apr 04, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) 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
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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 (Counsyl Autosomal Dominant Disease Classification criteria (2015)) 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	Publications: PubMed (6) PubMed: 25186627‚ 21835029‚ 23399955‚ 25318351‚ 22703879‚ 25637381
Likely benign (Aug 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) 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
Benign (Mar 09, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 (Mendelics Assertion Criteria 2017) 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 (Nov 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 10, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) 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 (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) 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 (ICSL Variant Classification Criteria 13 December 2019) 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 (ICSL Variant Classification Criteria 13 December 2019) 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 (Jan 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) 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	Publications: PubMed (1) PubMed: 32573726 Comment: BS1 +BP2 Number of individuals with the variant: 1
Benign (Feb 08, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) 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	Publications: PubMed (12) PubMed: 22703879‚ 25318351‚ 25980754‚ 25148578‚ 23399955‚ 21835029‚ 25186627‚ 27443514‚ 27153395‚ 25589618‚ 28196074‚ 30842500 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 (ACMG Guidelines, 2015) 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 (Sema4 Curation Guidelines) 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 (GeneDx Variant Classification Process June 2021) 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)
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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
Likely benign (May 10, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) 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	Publications: PubMed (11) PubMed: 32573726‚ 27443514‚ 25186627‚ 25148578‚ 22703879‚ 25637381‚ 25980754‚ 23399955‚ 27153395‚ 25318351‚ 21835029
Benign (Nov 06, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) 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 (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) 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
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	Publications: PubMed (1) PubMed: 22703879 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)
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
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	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
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, 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
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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 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:

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 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.

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:

Citations for germline classification of this variant

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 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_005359.6(SMAD4):c.1573A>G (p.Ile525Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149755320 ...