ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.424+5G>A (rs200772603)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656977 SCV000149792 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.424+5G>A or IVS3+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 3 of the SMAD4 gene. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant was identified in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps and in an individual with an advanced cancer (Yurgelun 2015, Mandelker 2017). This variant was observed at an allele frequency of 0.035% (44/126,306) in individuals of European ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether SMAD4 c.424+5G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115883 SCV000186740 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000204731 SCV000259352 uncertain significance Juvenile polyposis syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the SMAD4 gene. It does not directly change the encoded amino acid sequence of the SMAD4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs200772603, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with a history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127950). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Illumina Clinical Services Laboratory,Illumina RCV000346296 SCV000409087 likely benign Myhre syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000400215 SCV000409088 likely benign Juvenile Polyposis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000306889 SCV000409089 likely benign Osler hemorrhagic telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213004 SCV000602194 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing
Color RCV000115883 SCV000686539 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
Counsyl RCV000204731 SCV000786540 likely benign Juvenile polyposis syndrome 2018-05-23 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115883 SCV000822202 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770696 SCV000902173 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-11-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000213004 SCV000918223 likely benign not specified 2017-09-12 criteria provided, single submitter clinical testing Variant summary: The SMAD4 c.424+5G>A variant causes a missense change involving the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts the loss of an SRp55 binding motif. However, these predictions have yet to be confirmed by functional studies. The variant was found in the control population dataset of ExAC in 28/121076 control chromosomes at a frequency of 0.0002313, which is approximately 116 times the estimated maximal expected allele frequency of a pathogenic SMAD4 variant (0.000002), suggesting this variant is likely a benign polymorphism. This variant was reported in multiple patients with CRC and breast cancer with no strong evidence for causality and is considered to be non-pathogenic by some authors (Yurgelun_2015, Tung_2015, Jelsig_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign, until more definitive clinical and functional studies become available.

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