NM_005359.6(SMAD4):c.1523G>A (p.Gly508Asp) AND Generalized juvenile polyposis/juvenile polyposis coli

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 1, 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:: RCV000664319.5

Allele description [Variation Report for NM_005359.6(SMAD4):c.1523G>A (p.Gly508Asp)]

NM_005359.6(SMAD4):c.1523G>A (p.Gly508Asp)

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.1523G>A (p.Gly508Asp)

HGVS:

NC_000018.10:g.51078331G>A
NG_013013.2:g.115292G>A
NM_005359.6:c.1523G>AMANE SELECT
NP_005350.1:p.Gly508Asp
NP_005350.1:p.Gly508Asp
LRG_318t1:c.1523G>A
LRG_318:g.115292G>A
LRG_318p1:p.Gly508Asp
NC_000018.9:g.48604701G>A
NM_005359.5:c.1523G>A

Protein change:

G508D

Links:

dbSNP: rs1555687572

NCBI 1000 Genomes Browser:

rs1555687572

Molecular consequence:

NM_005359.6:c.1523G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Generalized juvenile polyposis/juvenile polyposis coli
Synonyms:: Juvenile polyposis coli
Identifiers:: MONDO: MONDO:0008276; MedGen: C1868081; Orphanet: 329971

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000788255	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Tsai GJ et al. (Genet Med 2018))	Likely pathogenic (May 1, 2018)	de novo	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000788255

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Tsai GJ et al. (Genet Med 2018))

Likely pathogenic
(May 1, 2018)

de novo

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	1	not provided	3	no	research

Citations

PubMed

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30374176

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000788255.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	research	PubMed (1)

Description

The SMAD4 variant designated as NM_005359.5:c.1523G>A (p.Gly508Asp) is as likely pathogenic. Testing in parents confirmed this variant be de novo in a patient with clinical history of juvenile polyposis syndrome beginning in their late teens and a negative family history for polyposis. This variant is highly conserved. It is not listed in population databases (ExAC or gnomAD). It is predicted to be damaging by in silico software programs (SIFT: â€œDamagingâ€, PolyPhen-2 â€œProbably Damagingâ€). The combined results are consistent with a classification of likely pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives 98% probability of pathogenicity, which is consistent with a classification of likely pathogenic. This variant is predicted to alter SMAD4 function and increase cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	3	not provided	not provided		1	not provided	1	not provided

Last Updated: Jun 23, 2024

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