ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1573A>G (p.Ile525Val) (rs149755320)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213006 SCV000149791 likely benign not specified 2017-12-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001420980 SCV000166566 likely benign Juvenile polyposis syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115882 SCV000187245 benign Cardiovascular phenotype 2018-11-06 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV000383039 SCV000409102 likely benign Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000123259 SCV000409103 likely benign Generalized juvenile polyposis/juvenile polyposis coli 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000327173 SCV000409104 likely benign Myhre syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213006 SCV000602192 likely benign not specified 2017-02-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000213006 SCV000605222 likely benign not specified 2018-12-19 criteria provided, single submitter clinical testing
Counsyl RCV000123259 SCV000784868 uncertain significance Generalized juvenile polyposis/juvenile polyposis coli 2017-01-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034710 SCV000806695 likely benign not provided 2017-08-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034710 SCV000889845 likely benign not provided 2020-02-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771070 SCV000902594 benign Hereditary cancer-predisposing syndrome 2016-03-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213006 SCV000918227 benign not specified 2021-02-08 criteria provided, single submitter clinical testing Variant summary: SMAD4 c.1573A>G (p.Ile525Val) results in a conservative amino acid change located in the SMAD domain, Dwarfin-type (IPR001132) of 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 0.00059 in 254026 control chromosomes, predominantly at a frequency of 0.00098 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 490 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 Latino origin. c.1573A>G has been reported in the literature in both non-cancer controls (example, Johnston_2012, Tram_2011) as well as in 2 patients with gastrointestinal polyposis (example, Ngeow_2013) and in others with cancer phenotypes and phenotypes not specified (example, Yorczyk_2015, Yurgelun_2015, Ring_2016, Maxwell_2016, Pelusi_2019, Tung_2015). The variant was also reported in somatic cancer tissues (example, Li_2015, Siroy_2015, Hamblin_2017). These report(s) do 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. 14 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The predominant consensus among all submitters is benign/likely benign (n=13). Based on the evidence outlined above and in alignment with the predominant consensus, the variant was classified as benign.
Mendelics RCV000123259 SCV001140895 benign Generalized juvenile polyposis/juvenile polyposis coli 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170612 SCV001333201 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-03-23 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000383039 SCV001439414 likely benign Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2018-01-01 criteria provided, single submitter research BS1 +BP2
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034710 SCV000043501 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148889 SCV000190634 likely benign Gastrointestinal polyposis 2014-06-01 no assertion criteria provided research
University of Washington Department of Laboratory Medicine, University of Washington RCV000383039 SCV001446374 benign Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2019-05-24 no assertion criteria provided research
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000034710 SCV001808810 likely benign not provided no assertion criteria provided clinical testing

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