Submissions for variant NM_005359.6(SMAD4):c.852A>G (p.Gln284=)

gnomAD frequency: 0.00008  dbSNP: rs144378484

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310724	SCV000212827	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2024-02-26	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001450056	SCV000254846	likely benign	Juvenile polyposis syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000200571	SCV000488072	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2015-12-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000417748	SCV000514708	benign	not specified	2015-05-05	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	RCV000162465	SCV000691440	likely benign	Hereditary cancer-predisposing syndrome	2016-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589728	SCV000698582	likely benign	not provided	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The SMAD4 c.852A>G (p.Gln284Gln) variant causes a synonymous change involving a conserved nucleotide with 4/5 splice prediction tools predicting an impact on splicing and ESE finder predicts that this variant may affect ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121408 (1/24283), predominantly in the European (Non-Finnish) cohort, 5/66740 (1/13347), which does exceed the estimated maximal expected allele frequency for a pathogenic SMAD4 variant of 1/500000. Therefore, suggesting the variant could be a common polymorphism found in population(s) of European (Non-Finnish) origin, however, this observation needs to be cautiously considered due to presence of a pseudogene possibly being captured. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. However, clinical diagnostic laboratories have cited the variant with conflicting classifications "likely benign" or "uncertain significance." Therefore, the variant of interest has been classified as "Likely Benign," until additional information becomes available (ie, clinical and/or functional studies).
Illumina Laboratory Services, Illumina	RCV001124423	SCV001283378	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001124424	SCV001283379	likely benign	Myhre syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000200571	SCV001283380	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000589728	SCV002063682	likely benign	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162465	SCV002538353	likely benign	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417748	SCV002551316	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001124423	SCV004017799	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	RCV001124423	SCV004820050	likely benign	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-12-13	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003330520	SCV004037536	not provided	Generalized juvenile polyposis/juvenile polyposis coli; Hereditary hemorrhagic telangiectasia		no assertion provided	phenotyping only	Variant classified as Likely benign and reported on 06-13-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.