Submissions for variant NM_005359.6(SMAD4):c.20C>T (p.Thr7Met)

gnomAD frequency: 0.00003  dbSNP: rs372316981

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310723	SCV000212786	benign	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001328507	SCV000254841	likely benign	Juvenile polyposis syndrome	2025-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000589285	SCV000293338	uncertain significance	not provided	2024-02-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26343384, 25559809, 28873162, 29684080)
Counsyl	RCV000196213	SCV000489675	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162438	SCV000686533	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 7 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 29684080). This variant has been identified in 15/282646 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	RCV002468936	SCV000698573	likely benign	not specified	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.20C>T (p.Thr7Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 1613528 control chromosomes. The observed variant frequency is approximately 2.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Colon Cancer phenotype (2.3e-05), strongly suggesting that the variant is benign. c.20C>T has been reported in the literature in at-least one individual affected with Colon Cancer (Chubb_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Colon and/or SMAD4-related Cancer. At-least one database (LOVD) publishes this variant as co-occuring with another variant 1244_1247delACAG in the SMAD4 gene. This co-occuring variant is annotated as SMAD4, c.1245_1248delCAGA (p.Asp415Glufs), a pathogenic variant in the ClinVar database. This provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 183733). Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000764159	SCV000895161	uncertain significance	Myhre syndrome; Generalized juvenile polyposis/juvenile polyposis coli; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001123230	SCV001282047	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2017-04-27	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001123231	SCV001282048	benign	Myhre syndrome	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000196213	SCV001283269	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2017-04-27	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589285	SCV002046218	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589285	SCV002048437	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	The SMAD4 c.20C>T; p.Thr7Met variant (rs372316981), is reported in the literature in an individual with colorectal cancer (Chubb 2015). This variant is reported in ClinVar (Variation ID: 183733) and is found in the general population with an overall allele frequency of 0.005% (15/282646 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.439). However, due to limited information, the clinical significance of the p.Thr7Met variant is uncertain at this time. References: Chubb D et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J Clin Oncol. 2015 Feb 10;33(5):426-32. PMID: 25559809.
Sema4, Sema4	RCV000162438	SCV002538316	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV001123230	SCV004017808	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV001123230	SCV004819995	uncertain significance	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 7 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 25559809, 29684080). This variant has been identified in 15/282646 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.
John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine	RCV002285148	SCV002575052	uncertain significance	Pulmonary arterial hypertension	2022-09-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398830	SCV004105918	uncertain significance	SMAD4-related disorder	2024-03-31	no assertion criteria provided	clinical testing	The SMAD4 c.20C>T variant is predicted to result in the amino acid substitution p.Thr7Met. This variant has been detected in at least one individual with a personal or family history of colon cancer (Chubb et al. 2015. PubMed ID: 25559809, Table A1). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations, ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/183733/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.