Submissions for variant NM_005359.6(SMAD4):c.332A>C (p.His111Pro)

gnomAD frequency: 0.00003  dbSNP: rs1064794363

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482083	SCV000568957	uncertain significance	not provided	2022-12-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235019, 18823382, 22992590)
Invitae	RCV000635412	SCV000756825	uncertain significance	Juvenile polyposis syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 111 of the SMAD4 protein (p.His111Pro). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 420231). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000482083	SCV000884548	uncertain significance	not provided	2017-10-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776540	SCV000912142	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-29	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 111 of the SMAD4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31402 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.
Ambry Genetics	RCV002446926	SCV001181421	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The p.H111P variant (also known as c.332A>C), located in coding exon 2 of the SMAD4 gene, results from an A to C substitution at nucleotide position 332. The histidine at codon 111 is replaced by proline, an amino acid with 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.