ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.471G>A (p.Met157Ile) (rs780716382)

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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 RCV000573873 SCV000672041 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000705291 SCV000834281 uncertain significance Juvenile polyposis syndrome 2018-04-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 157 of the SMAD4 protein (p.Met157Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs780716382, ExAC 0.01%). This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 484827). 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.
Color RCV000573873 SCV000904229 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780719 SCV000918228 likely benign not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: SMAD4 c.471G>A (p.Met157Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277138 control chromosomes. The observed variant frequency is approximately 10.82 fold above the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.471G>A in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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