ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.607C>G (p.Pro203Ala) (rs199809905)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561819 SCV000675135 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000160958 SCV000211667 uncertain significance not provided 2014-04-08 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.607C>G at the cDNA level, p.Pro203Ala (P203A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Pro203Ala 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 Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. SMAD4 Pro203Ala occurs at a position that is well conserved across species and is not located in a known functional domain. 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 Pro203Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000534543 SCV000632795 uncertain significance Juvenile polyposis syndrome 2017-10-31 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 203 of the SMAD4 protein (p.Pro203Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. 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: 182868). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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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