ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.643C>T (p.Pro215Ser) (rs1064793270)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486636 SCV000565581 uncertain significance not provided 2015-02-19 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.643C>T at the cDNA level, p.Pro215Ser (P215S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Pro215Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SMAD4 Pro215Ser occurs at a position that is highly conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether SMAD4 Pro215Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000775794 SCV000910245 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
Invitae RCV000807328 SCV000947375 uncertain significance Juvenile polyposis syndrome 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 215 of the SMAD4 protein (p.Pro215Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 418498). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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