Submissions for variant NM_005359.6(SMAD4):c.565C>T (p.Arg189Cys)

gnomAD frequency: 0.00104  dbSNP: rs140743238

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000122057	SCV000149793	likely benign	not specified	2017-11-08	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	RCV002310998	SCV000185945	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2018-11-08	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.
Invitae	RCV001507132	SCV000253436	benign	Juvenile polyposis syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000034711	SCV000333810	uncertain significance	not provided	2018-04-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000196842	SCV000487981	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2015-12-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000122057	SCV000602196	benign	not specified	2019-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122057	SCV000698577	benign	not specified	2021-03-22	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.565C>T (p.Arg189Cys) results in a non-conservative amino acid change in 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 0.0003 in 252626 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1800 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 a benign polymorphism found primarily in populations of African or African-American origin. c.565C>T has been reported in the literature in individuals affected with various cancer phenotypes (e.g. Ong_2014, Tung_2014, Wong_2015, Feldman_2016, Schubert_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.3860delA, p.Asn1287fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=5, VUS, n=2). At-least one submitter has re-evaluated this variant as benign since their previous submission as likely benign and some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging majority consensus among peers and the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000034711	SCV000806702	likely benign	not provided	2017-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115884	SCV000910626	likely benign	Hereditary cancer-predisposing syndrome	2016-05-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115884	SCV002538332	benign	Hereditary cancer-predisposing syndrome	2020-11-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122057	SCV002551309	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315550	SCV004017795	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034711	SCV000043500	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000122057	SCV000086268	not provided	not specified	2013-09-19	no assertion provided	reference population
Mayo Clinic Laboratories, Mayo Clinic	RCV000122057	SCV000692029	uncertain significance	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034711	SCV001924496	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034711	SCV001958939	likely benign	not provided		no assertion criteria provided	clinical testing