ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8266A>G (p.Ile2756Val)

gnomAD frequency: 0.00026  dbSNP: rs146115809
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002228439 SCV000166066 likely benign Familial adenomatous polyposis 1 2021-12-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148374 SCV000190068 uncertain significance Colorectal adenoma 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant belongs in a lower pathogenicity class
GeneDx RCV000587542 SCV000209559 likely benign not provided 2020-12-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21859464, 25637381, 18199528, 26332594, 28166811)
Counsyl RCV000122809 SCV000487910 uncertain significance Familial adenomatous polyposis 1 2015-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000493019 SCV000581417 likely benign Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001549270 SCV000694141 likely benign not specified 2021-07-12 criteria provided, single submitter clinical testing Variant summary: APC c.8266A>G (p.Ile2756Val) results in a conservative amino acid change located in the EB-1 binding of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 253078 control chromosomes. The observed variant frequency is approximately 1.3 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 benign. c.8266A>G has been reported in the literature in an individual affected with colorectal adenomas (example, Azzopardi_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=5; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000493019 SCV000911089 likely benign Hereditary cancer-predisposing syndrome 2016-05-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587542 SCV001133376 likely benign not provided 2021-06-06 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001157355 SCV001318917 likely benign APC-Associated Polyposis Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics RCV000122809 SCV001481389 uncertain significance Familial adenomatous polyposis 1 2020-02-23 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory,University of Chicago RCV001549270 SCV002069713 uncertain significance not specified 2021-07-19 criteria provided, single submitter clinical testing DNA sequence analysis of the APC gene demonstrated a sequence change, c.8266A>G, in exon 16 that results in an amino acid change, p.Ile2756Val. This sequence change has been previously described in an individual with colorectal adenoma, but no detailed information was provided (PMID: 18199528). This sequence change has been described in the gnomAD database in the African/African American subpopulation with a low frequency of 0.048% (dbSNP rs146115809). The p.Ile2756Val change affects a moderately conserved amino acid residue located in a domain of the APC protein that is known to be functional. The p.Ile2756Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile2756Val change remains unknown at this time.
Sema4,Sema4 RCV000493019 SCV002531681 likely benign Hereditary cancer-predisposing syndrome 2021-01-31 criteria provided, single submitter curation

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