Submissions for variant NM_005359.6(SMAD4):c.175A>G (p.Thr59Ala)

dbSNP: rs587781977

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310716	SCV000185225	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2020-12-17	criteria provided, single submitter	clinical testing	The p.T59A variant (also known as c.175A>G), located in coding exon 1 of the SMAD4 gene, results from an A to G substitution at nucleotide position 175. The threonine at codon 59 is replaced by alanine, an amino acid with similar properties. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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.
Counsyl	RCV000411833	SCV000489156	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV002228494	SCV000632775	uncertain significance	Juvenile polyposis syndrome	2022-01-16	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 141740). 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 alanine, which is neutral and non-polar, at codon 59 of the SMAD4 protein (p.Thr59Ala).
Color Diagnostics, LLC DBA Color Health	RCV000130371	SCV001339703	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 59 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.
Myriad Genetics, Inc.	RCV003315889	SCV004017818	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.