Submissions for variant NM_005359.6(SMAD4):c.1086T>C (p.Phe362=)

gnomAD frequency: 0.00228  dbSNP: rs1801250

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001507168	SCV000153829	benign	Juvenile polyposis syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000213005	SCV000171764	benign	not specified	2013-12-26	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	RCV002310676	SCV000212861	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2014-09-25	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.
Illumina Laboratory Services, Illumina	RCV000388633	SCV000409099	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	RCV000273483	SCV000409100	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001083846	SCV000409101	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587945	SCV000605223	benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128172	SCV000686513	benign	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587945	SCV000698561	benign	not provided	2016-02-23	criteria provided, single submitter	clinical testing	Variant summary: The c.1086T>C in SMAD4 gene is a synonymous change that involves a conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant was found in multiple affected individuals presented with personal and/or family history of cancer. It is present in the control population dataset of ExAC at frequency of 0.17%, including 2 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic SMAD4 variant, suggesting that it is a common polymorphism. However, some of these occurrences may potentially be due to a presence of a processed pseudogene, and, therefore, should be taken with cautions. Lastly, the variant has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken together, this variant has been classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000213005	SCV000806688	benign	not specified	2016-12-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000213005	SCV000860202	likely benign	not specified	2018-03-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587945	SCV000889838	benign	not provided	2022-08-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770698	SCV000902175	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-08-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000213005	SCV002067431	benign	not specified	2019-04-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587945	SCV002498379	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	SMAD4: BP4, BS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213005	SCV002552026	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001507168	SCV004015518	benign	Juvenile polyposis syndrome	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000213005	SCV000692036	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128172	SCV000788211	likely benign	Hereditary cancer-predisposing syndrome	2017-10-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001083846	SCV001548643	likely benign	Generalized juvenile polyposis/juvenile polyposis coli		no assertion criteria provided	clinical testing	The SMAD4 p.Phe362= variant was identified in 2 of 1004 proband chromosomes (frequency: 0.002) from individuals or families with gastric or breast cancer and was present in 1 of 1420 control chromosomes (frequency: 0.001) from healthy individuals (Oliveira 2003, Tram 2011). The variant was also identified in dbSNP (ID: rs1801250) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Color and ARUP; and as likely benign by Ambry Genetics and two other submitters), and in LOVD 3.0 (3x as benign or likely benign). The variant was identified in control databases in 502 of 277188 chromosomes (3 homozygous) at a frequency of 0.002, 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 84 of 24028 chromosomes (freq: 0.003), Other in 28 of 6466 chromosomes (freq: 0.004), Latino in 103 of 34412 chromosomes (freq: 0.003), European in 133 of 126694 chromosomes (freq: 0.001), Ashkenazi Jewish in 149 of 10150 chromosomes (freq: 0.02), and South Asian in 5 of 30782 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian or Finnish populations. The p.Phe362= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000213005	SCV001808084	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000213005	SCV001920674	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587945	SCV001957519	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587945	SCV001975360	likely benign	not provided		no assertion criteria provided	clinical testing