ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.677C>T (p.Ala226Val) (rs539739051)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160959 SCV000211668 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.677C>T at the cDNA level, p.Ala226Val (A226V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has been observed in one individual with breast and colon cancer and at least one other with breast and/or ovarian cancer (Pearlman 2017, Cock-Rada 2017). SMAD4 Ala226Val was observed at an allele frequency of 0.03% (4/44,556) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Ala226Val occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether SMAD4 Ala226Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000199953 SCV000254843 likely benign Juvenile polyposis syndrome 2019-12-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000199953 SCV000409096 uncertain significance Juvenile polyposis 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 RCV000449407 SCV000537608 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515353 SCV000611523 uncertain significance Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2017-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617134 SCV000671976 uncertain significance Cardiovascular phenotype 2019-01-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
True Health Diagnostics RCV000449407 SCV000805308 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing

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