ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.455-6A>G (rs181178864)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000153972 SCV000171763 benign not specified 2014-02-14 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153972 SCV000203597 benign not specified 2014-04-03 criteria provided, single submitter clinical testing
Invitae RCV001507245 SCV000262403 benign Juvenile polyposis syndrome 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000343024 SCV000409090 benign Myhre syndrome 2018-01-12 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 RCV001083669 SCV000409091 benign Generalized juvenile polyposis/juvenile polyposis coli 2018-01-12 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 RCV000303525 SCV000409092 benign Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2018-01-12 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000153972 SCV000602195 likely benign not specified 2017-04-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000153972 SCV000605221 benign not specified 2016-09-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580717 SCV000686540 benign Hereditary cancer-predisposing syndrome 2016-03-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000153972 SCV000806700 benign not specified 2017-12-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759347 SCV000888626 benign not provided 2018-05-24 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000153972 SCV000692028 benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001083669 SCV001549171 likely benign Generalized juvenile polyposis/juvenile polyposis coli no assertion criteria provided clinical testing The SMAD4 c.455-6A>G variant was identified in 1 of 2520 proband chromosomes (frequency: 0.00039) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs181178864) as "With other allele", ClinVar (classified as benign by GeneDx, Invitae, Color Genomics and two other submitters; as likely benign by two submitters), and in LOVD 3.0 (1x). The variant was not identified in Cosmic, or the ARUP database. The variant was identified in control databases in 251 of 276002 chromosomes (1 homozygous) at a frequency of 0.0009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 230 of 24002 chromosomes (freq: 0.01), Other in 3 of 6404 chromosomes (freq: 0.0005), Latino in 16 of 34254 chromosomes (freq: 0.0005), European in 2 of 125986 chromosomes (freq: 0.00002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.455-6A>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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