Submissions for variant NM_005359.6(SMAD4):c.917A>G (p.Asn306Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881953

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656978	SCV000211669	uncertain significance	not provided	2023-05-26	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; Identified in an individual with a personal history of appendiceal tumor and family history of breast cancer who was also homozygous for a pathogenic CHEK2 variant (Kidambi et al., 2017); This variant is associated with the following publications: (PMID: 26900293, 10636916, 28283864)
Ambry Genetics	RCV002310721	SCV000277930	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.N306S variant (also known as c.917A>G), located in coding exon 7 of the SMAD4 gene, results from an A to G substitution at nucleotide position 917. The asparagine at codon 306 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly 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.
Invitae	RCV000468723	SCV000543746	uncertain significance	Juvenile polyposis syndrome	2024-01-29	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 306 of the SMAD4 protein (p.Asn306Ser). This variant is present in population databases (rs730881953, gnomAD 0.007%). 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: 182870). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. 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	RCV000160960	SCV000602201	uncertain significance	not specified	2017-05-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217266	SCV000686565	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160960	SCV002551323	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485004	SCV002790382	uncertain significance	Myhre syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas; Juvenile polyposis syndrome	2021-09-14	criteria provided, single submitter	clinical testing