NM_005359.6(SMAD4):c.894del (p.Gly299fs) AND Juvenile polyposis syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 21, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001825132.4

Allele description [Variation Report for NM_005359.6(SMAD4):c.894del (p.Gly299fs)]

NM_005359.6(SMAD4):c.894del (p.Gly299fs)

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.894del (p.Gly299fs)

HGVS:

NC_000018.10:g.51058446del
NG_013013.2:g.95407del
NM_005359.6:c.894delMANE SELECT
NP_005350.1:p.Gly299fs
LRG_318t1:c.894del
LRG_318:g.95407del
NC_000018.9:g.48584814del
NC_000018.9:g.48584816del
NM_005359.5:c.894delC

Protein change:

G299fs

Links:

dbSNP: rs2144429392

NCBI 1000 Genomes Browser:

rs2144429392

Molecular consequence:

NM_005359.6:c.894del - 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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MICOS complex subunit MIC26 isoform X1 [Homo sapiens]
MICOS complex subunit MIC26 isoform X1 [Homo sapiens]
gi|2462631092|ref|XP_054183833.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002074442	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 26, 2022)	germline	clinical testing	Citation Link,
SCV003342155	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16152648, 16436638, 22810475, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002074442

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 26, 2022)

germline

clinical testing

Citation Link,

SCV003342155

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 21, 2022)

germline

clinical testing

PubMed (4)
[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

Vessels' morphology in SMAD4 and BMPR1A-related juvenile polyposis.

Handra-Luca A, Condroyer C, de Moncuit C, Tepper M, Fléjou JF, Thomas G, Olschwang S.

Am J Med Genet A. 2005 Oct 1;138A(2):113-7.

PubMed [citation]

PMID:: 16152648

Mutation screening in juvenile polyposis syndrome.

Pyatt RE, Pilarski R, Prior TW.

J Mol Diagn. 2006 Feb;8(1):84-8.

PubMed [citation]

PMID:: 16436638
PMCID:: PMC1867574

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074442.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: SMAD4 c.894delC (p.Gly299AspfsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been have been reported in patients affected with juvenile polyposis coli (HGMD). The variant was absent in 251444 control chromosomes (gnomAD). To our knowledge, no occurrence of c.894delC in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003342155.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1339744). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly299Aspfs*37) in the SMAD4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475).

#	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: Sep 29, 2024

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