NM_005359.6(SMAD4):c.1515del (p.Phe505fs) AND Juvenile polyposis syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 4, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001388771.6

Allele description

NM_005359.6(SMAD4):c.1515del (p.Phe505fs)

Gene:

SMAD4:SMAD family member 4 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

18q21.2

Genomic location:

Preferred name:

NM_005359.6(SMAD4):c.1515del (p.Phe505fs)

HGVS:

NC_000018.10:g.51078323del
NC_000018.9:g.48604690del
NG_013013.2:g.115284del
NM_005359.6:c.1515delMANE SELECT
NP_005350.1:p.Phe505fs
LRG_318:g.115284del
NC_000018.9:g.48604690del
NC_000018.9:g.48604690delT
NC_000018.9:g.48604693del
NM_005359.5:c.1512delT

Protein change:

F505fs

Links:

dbSNP: rs864622252

NCBI 1000 Genomes Browser:

rs864622252

Molecular consequence:

NM_005359.6:c.1515del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Juvenile polyposis syndrome (JPS)
Synonyms:: Polyposis juvenile intestinal; Polyposis familial of entire gastrointestinal tract
Identifiers:: MONDO: MONDO:0017380; MedGen: C0345893; Orphanet: 2929; OMIM: 174900

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optineurin [Homo sapiens]
optineurin [Homo sapiens]
gi|56549111|ref|NP_001008214.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001589901	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 4, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18178612, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001589901

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 4, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis.

van Hattem WA, Brosens LA, de Leng WW, Morsink FH, Lens S, Carvalho R, Giardiello FM, Offerhaus GJ.

Gut. 2008 May;57(5):623-7. doi: 10.1136/gut.2007.142927. Epub 2008 Jan 4.

PubMed [citation]

PMID:: 18178612

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001589901.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change results in a premature translational stop signal in the SMAD4 gene (p.Phe505Leufs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acids of the SMAD4 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. A different truncation (p.His530Thrfs*47) that lies downstream of this variant has been determined to be pathogenic (PMID: 18178612, Invitae). This suggests that deletion of this region of the SMAD4 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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