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

gnomAD frequency: 0.00005  dbSNP: rs757020188

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163203	SCV000213725	likely benign	Hereditary cancer-predisposing syndrome	2019-05-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233129	SCV000282834	likely benign	Familial adenomatous polyposis 1	2025-01-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000233129	SCV000489611	likely benign	Familial adenomatous polyposis 1	2016-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	benign	not provided	2022-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Sema4, Sema4	RCV000163203	SCV002530911	likely benign	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000233129	SCV004018643	benign	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV000759446	SCV004159231	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003895099	SCV004717307	likely benign	APC-related disorder	2023-09-27	no assertion criteria provided	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).