Submissions for variant NM_005359.6(SMAD4):c.1653A>G (p.Leu551=)

gnomAD frequency: 0.00004  dbSNP: rs199526820

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001450073	SCV000166568	likely benign	Juvenile polyposis syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310679	SCV000213183	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2014-10-24	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.
Counsyl	RCV000123261	SCV000489064	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2016-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000439984	SCV000514710	benign	not specified	2015-04-30	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.
Color Diagnostics, LLC DBA Color Health	RCV000162721	SCV000686529	likely benign	Hereditary cancer-predisposing syndrome	2016-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439984	SCV000920224	benign	not specified	2017-10-26	criteria provided, single submitter	clinical testing	Variant summary: The SMAD4 c.1653A>G (p.Leu551Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 13/276566 control chromosomes (gnomAD) at a frequency of 0.000047, which is approximately 24 times the estimated maximal expected allele frequency of a pathogenic SMAD4 variant (0.000002), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858658	SCV001134825	benign	not provided	2019-06-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123261	SCV001284608	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001125527	SCV001284609	likely 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 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	RCV001125528	SCV001284610	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Myriad Genetics, Inc.	RCV001125528	SCV004017787	benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
All of Us Research Program, National Institutes of Health	RCV001125528	SCV004820103	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-12-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894971	SCV004713863	likely benign	SMAD4-related disorder	2021-01-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).