ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.20C>T (p.Thr7Met) (rs372316981)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162438 SCV000212786 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000196213 SCV000254841 uncertain significance Juvenile polyposis syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 7 of the SMAD4 protein (p.Thr7Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs372316981, ExAC 0.02%). This variant has been reported in an individual with a personal and family history of colon cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 183733). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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 RCV000589285 SCV000293338 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.20C>T at the cDNA level, p.Thr7Met (T7M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was observed in an individual with a personal and family history of colorectal cancer and in at least one other individual with colon cancer (Chubb 2015, Yehia 2018). SMAD4 Thr7Met was observed at an allele frequency of 0.01% (3/25,766) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether SMAD4 Thr7Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000196213 SCV000489675 uncertain significance Juvenile polyposis syndrome 2016-11-08 criteria provided, single submitter clinical testing
Color RCV000162438 SCV000686533 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589285 SCV000698573 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The SMAD4 c.20C>T (p.Thr7Met) variant located in the MAD homology domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/121144 (1/15142), which exceeds the estimated maximal expected allele frequency for a pathogenic SMAD4 variant pf 1/500000. Therefore, suggesting this variant is likely a benign polymorphism, although this observation needs to be cautiously considered due to the possibility of the pseudogene being captured. A publication cites the variant in an affected individual diagnosed with Colorectal cancer, although cosegregation data was not provided. In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Fulgent Genetics,Fulgent Genetics RCV000764159 SCV000895161 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

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