ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.535A>G (p.Ile179Val) (rs542392980)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165366 SCV000216092 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient evidence
Counsyl RCV000233612 SCV000785419 uncertain significance Juvenile polyposis syndrome 2017-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764161 SCV000895163 uncertain significance Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000236451 SCV000292882 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.535A>G at the cDNA level, p.Ile179Val (I179V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been identified as a somatic variant in a lung tumor (Lee 2013). SMAD4 Ile179Val was not observed at a significant allele frequency in 1000 Genomes. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Ile179Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated 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 Ile179Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000233612 SCV000288876 uncertain significance Juvenile polyposis syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 179 of the SMAD4 protein (p.Ile179Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs542392980, ExAC 0.01%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 185866). 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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