ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.884C>T (p.Pro295Leu) (rs370176106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000576051 SCV000671984 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000576051 SCV000686563 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000479945 SCV000567362 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.884C>T at the cDNA level, p.Pro295Leu (P295L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. SMAD4 Pro295Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the SAD region (UniProt). 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 Pro295Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000234236 SCV000288882 uncertain significance Juvenile polyposis syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 295 of the SMAD4 protein (p.Pro295Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs370176106, ExAC 0.001%). This variant has not been reported in the literature in individuals with a SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 240155). 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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