ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7878T>G (p.Thr2626=) (rs757020188)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163203 SCV000213725 likely benign Hereditary cancer-predisposing syndrome 2014-10-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign,Co-occurence with mutation in same gene (phase unknown)
Invitae RCV000233129 SCV000282834 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change affects codon 2626 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. This variant is present in population databases (rs757020188, ExAC 0.007%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 184082). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
Counsyl RCV000233129 SCV000489611 likely benign Familial adenomatous polyposis 1 2016-10-31 criteria provided, single submitter clinical testing
Color RCV000163203 SCV000687149 likely benign Hereditary cancer-predisposing syndrome 2016-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000614044 SCV000729684 benign not specified 2015-09-10 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759446 SCV000888770 likely benign not provided 2017-07-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000614044 SCV000918473 benign not specified 2018-11-30 criteria provided, single submitter clinical testing Variant summary: APC c.7878T>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-05 in 276846 control chromosomes, predominantly at a frequency of 9.5e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.7878T>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing experience (Homozygous MUTYH c.536A>G, p.Tyr179Cys in a patient with colorectal polyposis and a strong family history), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.

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