Submissions for variant NM_005359.6(SMAD4):c.1052A>T (p.Asp351Val)

dbSNP: rs1060500741

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002230332	SCV000543754	uncertain significance	Juvenile polyposis syndrome	2016-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with valine at codon 351 of the SMAD4 protein (p.Asp351Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD4-related disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781852	SCV000920225	uncertain significance	not specified	2018-03-28	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.1052A>T (p.Asp351Val) results in a non-conservative amino acid change located in the dwarfin-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1052A>T has been reported in the literature in an individual with colorectal cancer (Adua 2017) and Juvenile Polyposis (Bishop 2017), however neither report provides strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002402237	SCV002706561	pathogenic	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2020-03-27	criteria provided, single submitter	clinical testing	The p.D351V pathogenic mutation (also known as c.1052A>T), located in coding exon 8 of the SMAD4 gene, results from an A to T substitution at nucleotide position 1052. The aspartic acid at codon 351 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with Juvenile Polyposis syndrome (JPS) (Ambry internal data). This variant has also been observed in individuals who have a personal or family history that is consistent with JPS (Ambry internal data). The same amino acid change has been reported in an individual with overlapping features of JPS and hereditary hemorrhagic telangiectasia (HTT) (Bishop JC et al. J Pediatr Genet, 2018 Jun;7:78-82). A different alteration in the same codon (p.D351H) has been observed in an individual with HTT (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003899904	SCV004713213	uncertain significance	SMAD4-related condition	2024-01-09	criteria provided, single submitter	clinical testing	The SMAD4 c.1052A>T variant is predicted to result in the amino acid substitution p.Asp351Val. This variant was reported in an individual with juvenile idiopathic arthritis with combined JP-HHT syndrome (Bishop et al. 2018. PubMed ID: 29707409) and in a tumor sample from an individual with colorectal cancer (Adua et al. 2017. PubMed ID: 28685087). This variant has not been reported in a large population database, indicating this variant is rare. It has conflicting interpretations of uncertain and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405499/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.