Submissions for variant NM_005359.6(SMAD4):c.715C>G (p.Gln239Glu)

dbSNP: rs1163381283

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581018	SCV000686552	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 239 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002413658	SCV001188409	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	The p.Q239E variant (also known as c.715C>G), located in coding exon 5 of the SMAD4 gene, results from a C to G substitution at nucleotide position 715. The glutamine at codon 239 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001215710	SCV001387469	uncertain significance	Juvenile polyposis syndrome	2023-01-26	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 490154). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 239 of the SMAD4 protein (p.Gln239Glu).
PreventionGenetics, part of Exact Sciences	RCV003983132	SCV004800199	uncertain significance	SMAD4-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The SMAD4 c.715C>G variant is predicted to result in the amino acid substitution p.Gln239Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.