ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.880A>G (p.Met294Val) (rs7238500)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617130 SCV000172948 likely benign Cardiovascular phenotype 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification,Other data supporting benign classification
Color RCV000129038 SCV000686562 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Counsyl RCV000195767 SCV000786418 likely benign Juvenile polyposis syndrome 2018-04-27 criteria provided, single submitter clinical testing
GeneDx RCV000586799 SCV000566288 uncertain significance not provided 2018-01-14 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.880A>G at the cDNA level, p.Met294Val (M294V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). SMAD4 Met294Val was observed at an allele frequency of 0.16% (39/23,898) in individuals of African ancestry in large population cohorts (Lek 2016), and in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the Bodian et al. study were younger than 50 years old, thus the unaffected status of this individual may not be significant. SMAD4 Met294Val is located within the SAD region (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether SMAD4 Met294Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000122058 SCV000086269 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000586799 SCV000698583 likely benign not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The SMAD4 c.880A>G (p.Met294Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 15/121398 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0012498 (13/10402). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic SMAD4 variant (0.000002), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant was reported in an individual who underwent genetics testing for Lynch syndrome, however without strong evidence for pathogenicity such as co-segregation. Multiple clinical diagnostic laboratories/reputable databases classified this variant as Likely benign/uncertain. Considering the high prevalence of the variant in the general population, it was classified as likely benign.
Invitae RCV000195767 SCV000253438 likely benign Juvenile polyposis syndrome 2018-01-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000122058 SCV000602200 uncertain significance not specified 2017-04-10 criteria provided, single submitter clinical testing

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