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

dbSNP: rs758642067

Total submissions: 5

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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	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.
Fulgent Genetics, Fulgent Genetics	RCV005029426	SCV005654195	uncertain significance	Myhre syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Familial pancreatic carcinoma; Juvenile polyposis syndrome	2024-06-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005231321	SCV005872296	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing