Submissions for variant NM_005359.6(SMAD4):c.693C>T (p.Gly231=)

gnomAD frequency: 0.00001  dbSNP: rs765597059

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001450082	SCV000253437	likely benign	Juvenile polyposis syndrome	2025-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000198986	SCV000489183	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2016-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000423609	SCV000515393	likely benign	not specified	2017-10-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002315626	SCV000675133	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2016-04-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Color Diagnostics, LLC DBA Color Health	RCV000564853	SCV000686550	likely benign	Hereditary cancer-predisposing syndrome	2017-06-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756668	SCV000884549	likely benign	not provided	2017-11-13	criteria provided, single submitter	clinical testing	The c.693C>T variant (rs765597059) does not alter the SMAD4 protein sequence and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site (Alamut software v2.7.1). This variant has not been reported in patients with aortopathy in medical literature or in gene specific variation databases and has been listed in ClinVar as likely benign (see link below). The c.693C>T variant is listed in the Exome Aggregation Consortium (ExAC) Browser with an overall population frequency of 0.002 percent (2 out of 120524 chromosomes). Thus, the c.693C>T variant is likely to be benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423609	SCV000918229	benign	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.693C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 276484 control chromosomes. The observed variant frequency is approximately 18.084 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.693C>T in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Myriad Genetics, Inc.	RCV003316107	SCV004017798	benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
All of Us Research Program, National Institutes of Health	RCV003316107	SCV004820041	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-03-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000423609	SCV000692030	likely benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955206	SCV004776634	likely benign	SMAD4-related disorder	2020-02-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).