Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001315123 | SCV001505679 | uncertain significance | Juvenile polyposis syndrome | 2021-08-17 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with asparagine at codon 227 of the SMAD4 protein (p.Ser227Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant has not been reported in the literature in individuals with SMAD4-related conditions. This variant is not present in population databases (ExAC no frequency). 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. |
| Ambry Genetics | RCV004557530 | SCV005048515 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2023-12-30 | criteria provided, single submitter | clinical testing | The p.S227N variant (also known as c.680G>A), located in coding exon 5 of the SMAD4 gene, results from a G to A substitution at nucleotide position 680. The serine at codon 227 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. 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. |