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

gnomAD frequency: 0.00026  dbSNP: rs146115809

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534364	SCV000166066	likely benign	Familial adenomatous polyposis 1	2024-02-01	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001549270	SCV000694141	likely benign	not specified	2022-11-22	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, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 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 African or African-American origin. c.8266A>G has been reported in the literature in an individual affected with colorectal adenomas (example, Azzopardi_2008). These reports 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. Ten 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=7, VUS n=3). 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	2023-08-09	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
Revvity Omics, Revvity	RCV000587542	SCV003826835	uncertain significance	not provided	2023-07-24	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153406	SCV003843476	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000122809	SCV004018754	likely benign	Familial adenomatous polyposis 1	2023-02-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001549270	SCV004025088	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing