Submissions for variant NM_005359.6(SMAD4):c.535A>G (p.Ile179Val)

gnomAD frequency: 0.00001  dbSNP: rs542392980

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311026	SCV000216092	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-07-22	criteria provided, single submitter	clinical testing	The p.I179V variant (also known as c.535A>G), located in coding exon 4 of the SMAD4 gene, results from an A to G substitution at nucleotide position 535. The isoleucine at codon 179 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in an individual affected with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This amino acid position is well 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	RCV001293445	SCV000288876	uncertain significance	Juvenile polyposis syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 179 of the SMAD4 protein (p.Ile179Val). This variant is present in population databases (rs542392980, gnomAD 0.008%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 185866). 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 with a negative predictive value of 95%. 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	RCV000236451	SCV000292882	uncertain significance	not provided	2023-10-01	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; Observed in an individual with a personal history of colorectal cancer (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 23559152, 15235019, 18823382, 22992590, 31837202, 26956206, 28135145)
Counsyl	RCV000233612	SCV000785419	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2017-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764161	SCV000895163	uncertain significance	Myhre syndrome; Generalized juvenile polyposis/juvenile polyposis coli; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165366	SCV001352931	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 179 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 been reported in an individual affected with colorectal cancer in the literature (PMID: 28135145). This variant has been identified in 4/282890 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.
Sema4, Sema4	RCV000165366	SCV002538330	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-18	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470782	SCV002768217	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with juvenile intestinal polyposis or juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MIM#174900, #175050), and Myhre syndrome (MIM#139210), respectively (OMIM, PMID: 31837202). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The variant p.(Ile179Phe) has been reported once as a variant of unknown significance in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in the ClinVar database 6 times as a variant of unknown significance (VUS). It has also been reported as a VUS in the germline of an individual with colorectal cancer (PMID: 28135145). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Myriad Genetics, Inc.	RCV002470782	SCV004017804	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.
Baylor Genetics	RCV002470782	SCV004202566	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-10-22	criteria provided, single submitter	clinical testing