Submissions for variant NM_005359.6(SMAD4):c.885G>A (p.Pro295=)

gnomAD frequency: 0.00001  dbSNP: rs772028872

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311909	SCV000671987	likely benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2016-12-27	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.
GeneDx	RCV000603480	SCV000730040	likely benign	not specified	2017-12-11	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.
Invitae	RCV000635495	SCV000756909	likely benign	Juvenile polyposis syndrome	2023-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000574603	SCV001356953	likely benign	Hereditary cancer-predisposing syndrome	2019-09-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574603	SCV002538356	likely benign	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478265	SCV004220368	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in individuals with SMAD4-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251436 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect SMAD4 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.