Submissions for variant NM_005359.6(SMAD4):c.910G>A (p.Val304Ile)

dbSNP: rs375185293

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001328505	SCV000259398	uncertain significance	Juvenile polyposis syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 304 of the SMAD4 protein (p.Val304Ile). This variant is present in population databases (rs375185293, gnomAD 0.0009%). 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: 219504). 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.
Counsyl	RCV000203937	SCV000489309	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001753607	SCV001995663	uncertain significance	not provided	2019-12-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002372194	SCV002684753	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-10-19	criteria provided, single submitter	clinical testing	The p.V304I variant (also known as c.910G>A), located in coding exon 7 of the SMAD4 gene, results from a G to A substitution at nucleotide position 910. The valine at codon 304 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly 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.
Myriad Genetics, Inc.	RCV003316126	SCV004017813	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.
Color Diagnostics, LLC DBA Color Health	RCV003584565	SCV004362357	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 304 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 hereditary cancer in the literature. This variant has been identified in 1/246170 chromosomes 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.