Submissions for variant NM_005359.6(SMAD4):c.800C>T (p.Thr267Ile)

dbSNP: rs1555685955

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506198	SCV000602199	uncertain significance	not specified	2016-09-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341290	SCV001535152	uncertain significance	Juvenile polyposis syndrome	2023-08-30	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 439298). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 267 of the SMAD4 protein (p.Thr267Ile).
Ambry Genetics	RCV002420280	SCV002680869	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	The p.T267I variant (also known as c.800C>T), located in coding exon 6 of the SMAD4 gene, results from a C to T substitution at nucleotide position 800. The threonine at codon 267 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003584638	SCV004362351	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 267 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.