ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.880A>G (p.Met294Val)

gnomAD frequency: 0.00050  dbSNP: rs7238500
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002310678 SCV000172948 likely benign Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2018-12-31 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.
Invitae RCV001450076 SCV000253438 likely benign Juvenile polyposis syndrome 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000586799 SCV000566288 likely benign not provided 2021-03-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24728327, 25980754, 22843233)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000122058 SCV000602200 uncertain significance not specified 2017-04-10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129038 SCV000686562 likely benign Hereditary cancer-predisposing syndrome 2020-03-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122058 SCV000698583 benign not specified 2019-05-24 criteria provided, single submitter clinical testing Variant summary: SMAD4 c.880A>G (p.Met294Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 282090 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 800 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.880A>G, was reported in one patient who underwent genetics testing for Lynch syndrome, however without strong evidence for pathogenicity (Yurgelun_2015). The report does not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000195767 SCV000786418 likely benign Generalized juvenile polyposis/juvenile polyposis coli 2018-04-27 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000586799 SCV002009678 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000129038 SCV002538355 likely benign Hereditary cancer-predisposing syndrome 2021-01-11 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV003315778 SCV004017800 likely benign Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2023-04-10 criteria provided, single submitter clinical testing This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
PreventionGenetics, part of Exact Sciences RCV003925209 SCV004751667 likely benign SMAD4-related condition 2021-02-03 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI RCV000122058 SCV000086269 not provided not specified 2013-09-19 no assertion provided reference population
Genetic Services Laboratory, University of Chicago RCV000122058 SCV003840069 likely benign not specified 2022-05-12 no assertion criteria provided clinical testing

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