ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.947A>G (p.Asn316Ser) (rs377119288)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132146 SCV000187217 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770697 SCV000902174 uncertain significance Thoracic aortic aneurysm and aortic dissection 2017-08-04 criteria provided, single submitter clinical testing
Color RCV000132146 SCV000686567 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Counsyl RCV000411125 SCV000488033 uncertain significance Juvenile polyposis syndrome 2015-12-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657009 SCV000706247 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing
GeneDx RCV000657009 SCV000566270 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.947A>G at the cDNA level, p.Asn316Ser (N316S) 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 colon polyps (Chang 2017). In addition, SMAD4 Asn316Ser was identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. SMAD4 Asn316Ser was observed at an allele frequency of 0.029% (9/30778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in 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 Asn316Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000122059 SCV000086270 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000411125 SCV000632813 uncertain significance Juvenile polyposis syndrome 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 316 of the SMAD4 protein (p.Asn316Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs377119288, ExAC 0.03%). This variant has been reported in an individual affected with polyps (PMID: 29069792). ClinVar contains an entry for this variant (Variation ID: 135245). 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, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000122059 SCV000602202 uncertain significance not specified 2017-05-19 criteria provided, single submitter clinical testing

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