Submissions for variant NM_005359.6(SMAD4):c.667+3G>A

gnomAD frequency: 0.00001  dbSNP: rs757971589

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000358363	SCV000409093	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.
Illumina Laboratory Services, Illumina	RCV000263575	SCV000409094	uncertain significance	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, 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	RCV000635437	SCV000409095	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.
Ambry Genetics	RCV002314055	SCV000675131	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2020-04-15	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.
Color Diagnostics, LLC DBA Color Health	RCV000571451	SCV000691425	likely benign	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001711942	SCV000730038	likely benign	not provided	2020-05-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26976419)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001328519	SCV000756850	likely benign	Juvenile polyposis syndrome	2023-12-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001711942	SCV004143104	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SMAD4: BP4
All of Us Research Program, National Institutes of Health	RCV000358363	SCV004821731	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000358363	SCV004931277	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.