ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1573A>G (p.Ile525Val) (rs149755320)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034710 SCV000605222 likely benign not provided 2017-06-01 criteria provided, single submitter clinical testing The p.Ile525Val variant (rs149755320) has been previously identified in patient cohorts tested due to clinical diagnoses of adenomatous and hyperplastic polyps (Ngeow 2013), breast cancer (Tram 2011), and unspecified hereditary cancer (Yorczyk 2015 and Yurgelun 2015). However, it has also been identified in one control population (Tram 2011), and in a cohort of atherosclerosis patients with no indicated personal or family history of cancer (Johnston 2012). This variant is also listed in the NHLBI GO Exome Sequencing Project (ESP) with an allele frequency in European Americans of 0.12% (identified in 10 out of 8,600 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with a frequency in Latino populations of 0.23% (identified in 27 out of 11,560 chromosomes). The isoleucine at codon 525 is highly conserved considering 15 species up to C. elegans (Alamut software v2.7.1), although due to similar physiochemical properties between valine and isoleucine, computational analyses suggest this variant does not have a significant effect on SMAD4 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Align-GVGD: C0). This variant is also not predicted to influence SMAD4 mRNA splicing. Additionally, three clinical laboratories have reported this variant to the ClinVar database with classification of likely benign (Variation ID: 41788). Thus, the p.Ile525Val variant is likely to be benign. References: Johnston et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012; 91(1): 97-108. Ngeow et al. Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. Gastroenterology. 2013; 144(7): 1402-1409. Tram et al. Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR). Breast Cancer Res. 2011; 13(4): R77. Yorczyk et al. Use of panel tests in place of single gene tests in the cancer genetics clinic. Clin Genet. 2015; 88(3): 278-282. Yurgelun et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015; 149(3): 604-13.e20.
Ambry Genetics RCV000115882 SCV000187245 likely benign Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Biesecker Lab/Human Development 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 Medical Center RCV000148889 SCV000190634 likely benign Gastrointestinal polyposis 2014-06-01 no assertion criteria provided research
Color RCV000771070 SCV000902594 benign Hereditary cancer-predisposing syndrome 2016-03-09 criteria provided, single submitter clinical testing
Counsyl RCV000123259 SCV000784868 uncertain significance Juvenile polyposis syndrome 2017-01-18 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000383039 SCV000409102 likely benign Osler hemorrhagic telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000291015 SCV000409103 likely benign Juvenile Polyposis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000327173 SCV000409104 likely benign Myhre syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000213006 SCV000918227 likely benign not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: SMAD4 c.1573A>G (p.Ile525Val) results in a conservative amino acid change located in the dwarfin-type domain (IPR001132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency in the gnomAD database (0.00054) is approximately 270 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. c.1573A>G has been reported in the literature in both non-cancer controls (Johnston 2012, Tram 2011) as well as in 2 patients with gastrointestinal polyposis (Ngeow 2013) and in others with cancer phenotypes and phenotypes not specified (Yorczyk 2015, Yurgelun 2015, Ring 2016, Maxwell 2016). The variant was also reported in somatic cancer tissues, however germline testing was not performed to rule out germline origin of the variant (Li 2015, Siroy 2015, Hamblin 2017). These reports do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000123259 SCV000166566 likely benign Juvenile polyposis syndrome 2017-12-22 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034710 SCV000806695 likely benign not provided 2017-08-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213006 SCV000602192 likely benign not specified 2017-02-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034710 SCV000889845 likely benign not provided 2018-03-29 criteria provided, single submitter clinical testing

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