Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002233865 | SCV000933992 | uncertain significance | Juvenile polyposis syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 229 of the SMAD4 protein (p.Leu229Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 24465802). ClinVar contains an entry for this variant (Variation ID: 641352). 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. |
Sema4, |
RCV002257956 | SCV002538342 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-06 | criteria provided, single submitter | curation | |
Ambry Genetics | RCV002360919 | SCV002665623 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2019-05-13 | criteria provided, single submitter | clinical testing | The p.L229R variant (also known as c.686T>G), located in coding exon 5 of the SMAD4 gene, results from a T to G substitution at nucleotide position 686. The leucine at codon 229 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly 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. |