Submissions for variant NM_005359.6(SMAD4):c.*11C>T

gnomAD frequency: 0.00538  dbSNP: rs11663402

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128174	SCV000171766	benign	not specified	2013-11-07	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.
PreventionGenetics, part of Exact Sciences	RCV000128174	SCV000311017	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000398463	SCV000409108	benign	Myhre syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000281314	SCV000409109	benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000338717	SCV000409110	benign	Generalized juvenile polyposis/juvenile polyposis coli	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000581104	SCV000686509	benign	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770700	SCV000902177	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2017-03-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001699207	SCV001156698	benign	not provided	2022-04-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000128174	SCV002067464	benign	not specified	2018-07-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001699207	SCV002546013	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SMAD4: BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000128174	SCV002551892	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128174	SCV004028920	benign	not specified	2023-07-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000128174	SCV000692041	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354685	SCV001549361	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The SMAD4 c.*11C>T variant was not identified in the literature nor was it identified in the ARUP Laboratories database. The variant was identified in dbSNP (ID: rs11663402) as "With other allele", ClinVar (classified as benign by Color Genomics, GeneDx, and PreventionGenetics; as likely benign by Mayo Clinic), and LOVD 3.0 (3x benign or likely benign). The variant was identified in control databases in 1416 of 275456 chromosomes (8 homozygous) at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 37 of 23968 chromosomes (freq: 0.002), Other in 30 of 6442 chromosomes (freq: 0.005), Latino in 177 of 34334 chromosomes (freq: 0.005), European in 987 of 125862 chromosomes (freq: 0.008), Ashkenazi Jewish in 71 of 10094 chromosomes (freq: 0.007), Finnish in 97 of 25220 chromosomes (freq: 0.004), and South Asian in 17 of 30714 chromosomes (freq: 0.0006), but was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000128174	SCV001918852	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699207	SCV001926764	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000128174	SCV001953038	benign	not specified		no assertion criteria provided	clinical testing