ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.700A>C (p.Ser234Arg)

dbSNP: rs758642067
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000775642 SCV000910020 uncertain significance Hereditary cancer-predisposing syndrome 2021-03-22 criteria provided, single submitter clinical testing This missense variant replaces serine with arginine at codon 234 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 1/251404 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 RCV002397549 SCV001188199 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2022-06-16 criteria provided, single submitter clinical testing The p.S234R variant (also known as c.700A>C), located in coding exon 5 of the SMAD4 gene, results from an A to C substitution at nucleotide position 700. The serine at codon 234 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an individual with aortopathy from China (Yang H et al. Sci Rep, 2016 09;6:33002). This amino acid position is well 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 RCV001052363 SCV001216572 uncertain significance Juvenile polyposis syndrome 2023-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 234 of the SMAD4 protein (p.Ser234Arg). This variant is present in population databases (rs758642067, gnomAD 0.006%). This missense change has been observed in individual(s) with aortopathy (PMID: 27611364). ClinVar contains an entry for this variant (Variation ID: 630393). 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 with a negative predictive value of 95%. 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.

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