Submissions for variant NM_005359.6(SMAD4):c.466A>T (p.Met156Leu)

gnomAD frequency: 0.00011  dbSNP: rs534355764

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464936	SCV000543763	likely benign	Juvenile polyposis syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311769	SCV000671972	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2021-01-08	criteria provided, single submitter	clinical testing	The p.M156L variant (also known as c.466A>T), located in coding exon 4 of the SMAD4 gene, results from an A to T substitution at nucleotide position 466. The methionine at codon 156 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000570776	SCV000691419	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 156 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer in the literature (PMID: 28944238). This variant has been identified in 5/282804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781854	SCV000920227	uncertain significance	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.466A>T (p.Met156Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.466A>T in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001566748	SCV001790314	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (DeRycke et al., 2017); This variant is associated with the following publications: (PMID: 18823382, 22992590, 15235019, 28944238)
Sema4, Sema4	RCV000570776	SCV002538327	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	criteria provided, single submitter	curation