ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.647A>G (p.Asn216Ser)

gnomAD frequency: 0.00002  dbSNP: rs138386557
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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 RCV002310733 SCV000214651 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2022-08-26 criteria provided, single submitter clinical testing The p.N216S variant (also known as c.647A>G), located in coding exon 4 of the SMAD4 gene, results from an A to G substitution at nucleotide position 647. The asparagine at codon 216 is replaced by serine, an amino acid with highly similar properties. In a study of 98 patients from high-risk colorectal cancer families, without mutations in the mismatch repair genes, this variant was seen in one patient, who met the Bethesda criteria (Martin-Morales L et al. PLoS ONE. 2018 Sep;13:e0203885). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000686995 SCV000814542 uncertain significance Juvenile polyposis syndrome 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 216 of the SMAD4 protein (p.Asn216Ser). This variant is present in population databases (rs138386557, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 184736). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 Diagnostics, LLC DBA Color Health RCV000164044 SCV000911393 benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000164044 SCV002538339 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-06 criteria provided, single submitter curation
GeneDx RCV004589740 SCV005080066 uncertain significance not provided 2023-11-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual from a high-risk colorectal cancer family (PMID: 30256826); This variant is associated with the following publications: (PMID: 15235019, 18823382, 22992590, 30256826)

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