ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.424+5G>A (rs200772603)

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Total submissions: 13
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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 likely benign Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing RNA Studies;Other data supporting benign classification
Invitae RCV000204731 SCV000259352 uncertain significance Juvenile polyposis syndrome 2020-01-02 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 benign Myhre syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000204731 SCV000409088 likely benign Juvenile polyposis syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000306889 SCV000409089 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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 2020-04-27 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 Familial 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000213004 SCV001157713 uncertain significance not specified 2018-07-23 criteria provided, single submitter clinical testing The SMAD4 c.424+5G>A variant (rs200772603) is reported in the literature in an individual with suspected Lynch syndrome (Yurgelun 2015), but it is also found in the general population with an overall allele frequency of 0.02% (55/276488 alleles) in the Genome Aggregation Database. This variant is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 127950). This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.424+5G>A variant is uncertain at this time. REFERENCES Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

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