ClinVar Miner

Submissions for variant NM_005359.5(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
Ambry Genetics RCV000617134 SCV000671976 uncertain significance Cardiovascular phenotype 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000449407 SCV000537608 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 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
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.
Illumina Clinical Services Laboratory,Illumina RCV000354960 SCV000409096 likely benign Juvenile Polyposis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000260140 SCV000409097 likely benign Osler hemorrhagic telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334040 SCV000409098 likely benign Myhre syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000199953 SCV000254843 uncertain significance Juvenile polyposis syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 226 of the SMAD4 protein (p.Ala226Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs539739051, ExAC 0.03%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 182869). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
True Health Diagnostics RCV000449407 SCV000805308 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing

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