ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.917A>G (p.Asn306Ser) (rs730881953)

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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 RCV000217266 SCV000277930 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000217266 SCV000686565 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000656978 SCV000211669 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.917A>G at the cDNA level, p.Asn306Ser (N306S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in an individual with an appendiceal carcinoid tumor and family history of breast cancer, who was also homozygous for a CHEK2 pathogenic variant (Kidambi 2017). SMAD4 Asn306Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SMAD4 activation domain (SAD) (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 Asn306Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000468723 SCV000543746 uncertain significance Juvenile polyposis syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 306 of the SMAD4 protein (p.Asn306Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs730881953, ExAC 0.01%). 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: 182870). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on SMAD4 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160960 SCV000602201 uncertain significance not specified 2017-05-29 criteria provided, single submitter clinical testing

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