Submissions for variant NM_005359.6(SMAD4):c.566G>A (p.Arg189His)

gnomAD frequency: 0.00001  dbSNP: rs759288477

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002231713	SCV000632794	uncertain significance	Juvenile polyposis syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 189 of the SMAD4 protein (p.Arg189His). This variant is present in population databases (rs759288477, gnomAD 0.004%). This missense change has been observed in individual(s) with colon cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 460557). 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.
Color Diagnostics, LLC DBA Color Health	RCV000579689	SCV000686544	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 189 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 performed for this variant. This variant has been reported in an individual affected with colorectal cancer who also carried a pathogenic variant in the BRCA2 gene (PMID: 28135145). This variant has been identified in 5/282872 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.
Fulgent Genetics, Fulgent Genetics	RCV000764162	SCV000895164	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
Ambry Genetics	RCV002319530	SCV001186395	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001584257	SCV001819251	uncertain significance	not provided	2022-09-09	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 conjunction with a BRCA2 pathogenic variant in an individual with a personal history of colon cancer and CLL and family history of ovarian and hematologic cancers (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 28135145)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001584257	SCV002009681	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268143	SCV002551310	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing