Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV002311911 | SCV000671992 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2021-03-08 | criteria provided, single submitter | clinical testing | The p.T222A variant (also known as c.664A>G), located in coding exon 4 of the SMAD4 gene, results from an A to G substitution at nucleotide position 664. The threonine at codon 222 is replaced by alanine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000986027 | SCV001134827 | uncertain significance | not provided | 2018-11-02 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001370742 | SCV001567274 | uncertain significance | Juvenile polyposis syndrome | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 222 of the SMAD4 protein (p.Thr222Ala). This variant is present in population databases (rs770461626, gnomAD 0.0009%). This missense change has been observed in individual(s) with kidney cancer (PMID: 29684080). ClinVar contains an entry for this variant (Variation ID: 484795). 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. |
Gene |
RCV000986027 | SCV004022972 | uncertain significance | not provided | 2023-01-26 | criteria provided, single submitter | clinical testing | Identified in a case from The Cancer Genome Atlas (TCGA) with kidney renal papillary cell carcinoma (Yehia et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15235019, 18823382, 22992590, 29684080) |
Color Diagnostics, |
RCV003584663 | SCV004362341 | likely benign | Hereditary cancer-predisposing syndrome | 2016-03-24 | criteria provided, single submitter | clinical testing |