Submissions for variant NM_005359.6(SMAD4):c.521C>A (p.Thr174Asn)

gnomAD frequency: 0.00014  dbSNP: rs138800446

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001312225	SCV000218932	likely benign	Juvenile polyposis syndrome	2024-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000236619	SCV000293595	uncertain significance	not provided	2023-07-02	criteria provided, single submitter	clinical testing	Has not been previously reported as a pathogenic or benign germline variant to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27363283, 25178641)
Ambry Genetics	RCV002312698	SCV000671971	benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000567416	SCV000686542	likely benign	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000168261	SCV000786392	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2018-04-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000236619	SCV001474189	uncertain significance	not provided	2020-04-14	criteria provided, single submitter	clinical testing	The SMAD4 c.521C>A; p.Thr174Asn variant (rs138800446), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 188279). This variant is found in the African population with an allele frequency of 0.052% (13/24966 alleles) in the Genome Aggregation Database. The threonine at codon 174 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr174Asn variant is uncertain at this time.
Sema4, Sema4	RCV000567416	SCV002538329	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-30	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281990	SCV002572234	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.521C>A (p.Thr174Asn) results in a non-conservative amino acid change located in the MAD homology 1, Dwarfin-type domain (IPR003619) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.521C>A in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003316069	SCV004017794	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.