18-51047066-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_005359.6(SMAD4):c.20C>T(p.Thr7Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000645 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T7R) has been classified as Uncertain significance.
Frequency
Consequence
NM_005359.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.20C>T | p.Thr7Met | missense_variant | 2/12 | ENST00000342988.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.20C>T | p.Thr7Met | missense_variant | 2/12 | 5 | NM_005359.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251288Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135810
GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461296Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 727010
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74446
ClinVar
Submissions by phenotype
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 10, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2023 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 09, 2023 | 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. - |
Generalized juvenile polyposis/juvenile polyposis coli Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 08, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 10, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 06, 2021 | - - |
Pulmonary arterial hypertension Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine | Sep 26, 2022 | - - |
SMAD4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2023 | 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 (http://gnomad.broadinstitute.org/variant/18-48573436-C-T). 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. - |
Carcinoma of pancreas;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;C1868081:Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Juvenile polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 7 of the SMAD4 protein (p.Thr7Met). This variant is present in population databases (rs372316981, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of colon cancer (PMID: 25559809, 29684080). ClinVar contains an entry for this variant (Variation ID: 183733). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 19, 2024 | 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. - |
Myhre syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at