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 benign Juvenile polyposis syndrome 2024-09-14 criteria provided, single submitter clinical testing
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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