Submissions for variant NM_005359.6(SMAD4):c.470T>C (p.Met157Thr)

gnomAD frequency: 0.00001  dbSNP: rs756675590

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587176	SCV000698575	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The SMAD4 c.470T>C (p.Met157Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/121274 control chromosomes at a frequency of 0.0000165, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic SMAD4 variant (0.000002), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.
Ambry Genetics	RCV002319047	SCV001184736	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2018-09-10	criteria provided, single submitter	clinical testing	The p.M157T variant (also known as c.470T>C), located in coding exon 4 of the SMAD4 gene, results from a T to C substitution at nucleotide position 470. The methionine at codon 157 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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	RCV001039892	SCV001203442	uncertain significance	Juvenile polyposis syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 157 of the SMAD4 protein (p.Met157Thr). This variant is present in population databases (rs756675590, gnomAD 0.003%). 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: 496289). 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.
GeneDx	RCV000587176	SCV003921370	uncertain significance	not provided	2022-10-27	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18823382, 22992590, 15235019)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321692	SCV004026934	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003392425	SCV004109968	uncertain significance	SMAD4-related condition	2023-02-14	criteria provided, single submitter	clinical testing	The SMAD4 c.470T>C variant is predicted to result in the amino acid substitution p.Met157Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-48581166-T-C). In ClinVar, it is interpreted as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/496289/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.