ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1081C>T (p.Arg361Cys) (rs80338963)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571896 SCV000671966 pathogenic Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Database of Curated Mutations (DoCM) RCV000424666 SCV000504610 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434956 SCV000504611 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419013 SCV000504612 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429075 SCV000504613 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435832 SCV000504614 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419899 SCV000504615 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430148 SCV000504616 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440366 SCV000504617 likely pathogenic Uterine cervical neoplasms 2016-05-31 no assertion criteria provided literature only
GeneReviews RCV000009071 SCV000041148 pathologic Juvenile polyposis syndrome 2011-09-29 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000009071 SCV000218955 pathogenic Juvenile polyposis syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 361 of the SMAD4 protein (p.Arg361Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals with either juvenile polyposis syndrome (JPS) or hereditary hemorrhagic telangiectasia (HHT), and in individuals with features of both JPS and HHT (PMID: 9811934, 16613914, 10764709, 17873119, 20101697). ClinVar contains an entry for this variant (Variation ID: 8543). Experimental studies have shown that this missense change disrupts protein binding, leading to an unstable SMAD4 protein subject to degradation (PMID: 9214508, 11583957). Different missense substitutions at this codon (p.Arg361Gly, p.Arg361His, p.Arg361Leu, p.Arg361Ser) have been determined to be pathogenic (PMID: 15031030, 10797267, 20101697, 15235019, 22316667). This suggests that the arginine residue is critical for SMAD4 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009071 SCV000029288 pathogenic Juvenile polyposis syndrome 2006-10-01 no assertion criteria provided literature only
OMIM RCV000009072 SCV000029289 pathogenic Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2006-10-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021711 SCV000042377 pathogenic JP, JP/HHT, and HHT 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
UniProtKB/Swiss-Prot RCV000059732 SCV000091302 not provided not provided no assertion provided not provided

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