ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.677C>T (p.Ala226Val)

gnomAD frequency: 0.00001  dbSNP: rs539739051
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160959 SCV000211668 uncertain significance not provided 2023-02-03 criteria provided, single submitter clinical testing Observed in individuals with a personal history of colon cancer and other cancers, but has not been reported in association with heritable disorders of connective tissue to our knowledge (Pearlman et al., 2017; Yurgelun et al., 2017; Cock-Rada et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28528518, 27978560, 28135145, 18823382, 22992590, 15235019)
Invitae RCV001420989 SCV000254843 likely benign Juvenile polyposis syndrome 2024-01-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000199953 SCV000409096 uncertain significance Generalized juvenile polyposis/juvenile polyposis coli 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000260140 SCV000409097 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000334040 SCV000409098 likely benign Myhre syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health RCV000449407 SCV000537608 likely benign Hereditary cancer-predisposing syndrome 2021-09-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000515353 SCV000611523 uncertain significance Myhre syndrome; Generalized juvenile polyposis/juvenile polyposis coli; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2017-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV002312690 SCV000671976 likely benign Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2020-05-11 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.
Sema4, Sema4 RCV000449407 SCV002538341 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-16 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000160959 SCV002822462 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing SMAD4: BP4
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160959 SCV004220361 likely benign not provided 2023-04-27 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000449407 SCV000805308 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV003483531 SCV004228559 not provided Myhre syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome no assertion provided phenotyping only Variant interpreted as Likely benign and reported on 01-28-2020 by Lab 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.

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