Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002310816 | SCV000278085 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2018-08-03 | criteria provided, single submitter | clinical testing | The p.C363Y variant (also known as c.1088G>A), located in coding exon 8 of the SMAD4 gene, results from a G to A substitution at nucleotide position 1088. The cysteine at codon 363 is replaced by tyrosine, an amino acid with highly dissimilar properties. Crystal structure analysis showed that this residue interacts with Arg361 which contacts SMAD2/3 (Fleming N et al. Cancer Res. 2013 Jan; 73(2):725-35). The p.C363Y variant has been detected in individuals with a personal and/or family history consistent with juvenile polyposis syndrome (JPS) (Ambry internal data). Another alteration at the same codon, p.C363R, has been described in individuals with clinical Juvenile Polyposis syndrome (JPS) (Aretz S et al. J. Med. Genet. 2007 Nov;44(11):702-9; Ngeow J et al. Gastroenterology 2013 Jun;144(7):1402-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001071904 | SCV001237236 | likely pathogenic | Juvenile polyposis syndrome | 2023-06-16 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys363 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17873119, 23805858). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD4 function. ClinVar contains an entry for this variant (Variation ID: 233663). This missense change has been observed in individuals with clinical features of SMAD4-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 363 of the SMAD4 protein (p.Cys363Tyr). |