NM_005359.6(SMAD4):c.812G>A (p.Ser271Asn) AND Juvenile polyposis syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 25, 2022
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:: RCV002234499.11

Allele description [Variation Report for NM_005359.6(SMAD4):c.812G>A (p.Ser271Asn)]

NM_005359.6(SMAD4):c.812G>A (p.Ser271Asn)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

18q21.2

Genomic location:

Preferred name:

NM_005359.6(SMAD4):c.812G>A (p.Ser271Asn)

HGVS:

NC_000018.10:g.51058364G>A
NG_013013.2:g.95325G>A
NM_005359.6:c.812G>AMANE SELECT
NP_005350.1:p.Ser271Asn
NP_005350.1:p.Ser271Asn
LRG_318t1:c.812G>A
LRG_318:g.95325G>A
LRG_318p1:p.Ser271Asn
NC_000018.9:g.48584734G>A
NM_005359.5:c.812G>A

Protein change:

S271N

Links:

dbSNP: rs1343555503

NCBI 1000 Genomes Browser:

rs1343555503

Molecular consequence:

NM_005359.6:c.812G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Homologene neighbors for GEO Profiles (Select 67629937) (0)
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Profile neighbors for GEO Profiles (Select 67612126) (199)
GEO Profiles
Synthetic construct clone IMAGE:100006306; FLH188215.01X; RZPDo839H09150D nuclea...
Synthetic construct clone IMAGE:100006306; FLH188215.01X; RZPDo839H09150D nuclear transcription factor, X-box binding 1 (NFX1) gene, encodes complete protein
gi|123994000|gb|DQ893676.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000756875	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28716708, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000756875

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 25, 2022)

germline

clinical testing

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

Help

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

Functional characteristics of a novel SMAD4 mutation from thoracic aortic aneurysms (TAA).

Wu L.

Gene. 2017 Sep 10;628:129-133. doi: 10.1016/j.gene.2017.07.042. Epub 2017 Jul 14.

PubMed [citation]

PMID:: 28716708

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000756875.4

#	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 replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 271 of the SMAD4 protein (p.Ser271Asn). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with thoracic aortic aneurysm (PMID: 28716708). ClinVar contains an entry for this variant (Variation ID: 529933). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SMAD4 function (PMID: 28716708). 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.

#	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: Nov 3, 2024

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