Submissions for variant NM_005359.6(SMAD4):c.354G>A (p.Ala118=)

gnomAD frequency: 0.00268  dbSNP: rs145988618

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507222	SCV000153894	benign	Juvenile polyposis syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000213003	SCV000171762	benign	not specified	2014-01-08	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	RCV002310631	SCV000212976	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2014-07-24	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.
Illumina Laboratory Services, Illumina	RCV000349756	SCV000409084	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	RCV000021679	SCV000409085	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.
Illumina Laboratory Services, Illumina	RCV000291347	SCV000409086	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679589	SCV000605224	benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128170	SCV000686537	likely benign	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679589	SCV000806699	likely benign	not provided	2016-07-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679589	SCV000888625	benign	not provided	2022-07-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679589	SCV000892508	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SMAD4: BP4, BP7, BS1, BS2
Genetic Services Laboratory, University of Chicago	RCV000213003	SCV002067420	benign	not specified	2018-07-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128170	SCV002538321	benign	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213003	SCV002551306	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000213003	SCV000692027	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128170	SCV000788213	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357816	SCV001553401	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The SMAD4 p.Ala118= variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with Juvenile polyposis syndrome (Pyatt 2006). The variant was also identified in dbSNP (ID: rs145988618) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, and ARUP; as likely benign by 7 submitters), Cosmic (2X in large intestine tissue), LOVD 3.0 (4x as benign or likely benign), and in ARUP Laboratories (as benign). The variant was identified in control databases in 768 of 277174 chromosomes (3 homozygous) at a frequency of 0.003 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 23 of 24032 chromosomes (freq: 0.0009), Other in 13 of 6462 chromosomes (freq: 0.002), Latino in 21 of 34418 chromosomes (freq: 0.0006), European in 572 of 126678 chromosomes (freq: 0.005), Ashkenazi Jewish in 3 of 10150 chromosomes (freq: 0.0003), Finnish in 132 of 25786 chromosomes (freq: 0.005), and South Asian in 4 of 30782 chromosomes (freq: 0.0001); it was not observed in the East Asian, population. The p.Ala118= 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000679589	SCV001739712	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000213003	SCV001809089	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000213003	SCV001919714	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679589	SCV001957347	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679589	SCV001972473	likely benign	not provided		no assertion criteria provided	clinical testing