ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.664A>G (p.Thr222Ala)

dbSNP: rs770461626
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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.
GeneDx 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, LLC DBA Color Health RCV003584663 SCV004362341 likely benign Hereditary cancer-predisposing syndrome 2016-03-24 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.