Submissions for variant NM_000038.6(APC):c.6525A>G (p.Thr2175=)

gnomAD frequency: 0.00009  dbSNP: rs200151646

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004567033	SCV000153926	benign	Familial adenomatous polyposis 1	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001310856	SCV000209478	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23709753, 28526081)
Ambry Genetics	RCV000159521	SCV000214464	likely benign	Hereditary cancer-predisposing syndrome	2015-01-01	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.
Illumina Laboratory Services, Illumina	RCV000374754	SCV000452036	uncertain significance	APC-Associated Polyposis Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254629	SCV000600129	uncertain significance	not specified	2016-07-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159521	SCV000681805	likely benign	Hereditary cancer-predisposing syndrome	2016-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254629	SCV000918460	benign	not specified	2017-10-31	criteria provided, single submitter	clinical testing	Variant Summary: The c.6525A>G (p.Thr2175Thr) variant involves the alteration of a non-conserved nucleotide resulting in a synonymous change. 4/5 in silico tools via Alamut predict the strengthening of a cryptic splice donor site as well as minor changes to other binding motifs, however, the significance of these predictions has not been supported with functional studies. The variant was observed in the general population dataset of gnomAD at an allele frequency of 0.00011 (32/275542 chromosomes tested), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0002 (26/126026 chromosomes). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in APC (0.00007) by 3-folds, strongly supporting that this is a benign polymorphism found primarily in population(s) of European origin. The variant has been reported once in the literature in a CRC patient without strong evidence for or against pathogenicity (Borras_2013). In addition, multiple clinical laboratories/reputable databases have classified the variant as likely benign. Taken together, this variant has been classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001310856	SCV001500826	likely benign	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159521	SCV002528774	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254629	SCV004243253	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997303	SCV004843412	likely benign	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004567033	SCV005084451	benign	Familial adenomatous polyposis 1	2024-04-05	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.
PreventionGenetics, part of Exact Sciences	RCV003915184	SCV004729787	likely benign	APC-related disorder	2020-02-07	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).