Submissions for variant NM_000038.6(APC):c.5027G>C (p.Arg1676Thr)

gnomAD frequency: 0.00033  dbSNP: rs143674116

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130120	SCV000184952	likely benign	Hereditary cancer-predisposing syndrome	2019-01-28	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.
GeneDx	RCV000589678	SCV000292990	likely benign	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Invitae	RCV003534378	SCV000552750	likely benign	Familial adenomatous polyposis 1	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000722124	SCV000694068	benign	not specified	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: APC c.5027G>C (p.Arg1676Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250184 control chromosomes, predominantly at a frequency of 0.0011 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 15.4 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. To our knowledge, no occurrence of c.5027G>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: four classified the variant as likely benign and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000130120	SCV000902908	likely benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000722124	SCV001469311	benign	not specified	2020-08-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925277	SCV004744664	likely benign	APC-related condition	2023-10-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).