Submissions for variant NM_000038.6(APC):c.7786T>G (p.Ser2596Ala)

gnomAD frequency: 0.00004  dbSNP: rs138137162

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131566	SCV000186570	likely benign	Hereditary cancer-predisposing syndrome	2019-02-13	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.
Invitae	RCV000229880	SCV000282830	likely benign	Familial adenomatous polyposis 1	2024-01-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000229880	SCV000489526	uncertain significance	Familial adenomatous polyposis 1	2016-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000656752	SCV000564585	likely benign	not provided	2021-04-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25604157, 25710373, 27443514, 30404791, 29684080)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656752	SCV000600160	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000478677	SCV000602506	uncertain significance	not specified	2016-09-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000229880	SCV000838156	benign	Familial adenomatous polyposis 1	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131566	SCV000902902	likely benign	Hereditary cancer-predisposing syndrome	2016-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478677	SCV000918472	likely benign	not specified	2018-11-30	criteria provided, single submitter	clinical testing	Variant summary: APC c.7786T>G (p.Ser2596Ala) results in a conservative amino acid change in 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 4e-05 in 276400 control chromosomes, predominantly at a frequency of 8.7e-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 1.22 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. c.7786T>G has been reported in the literature in individuals affected with colorectal polyps, ovarian and endometrial cancer (Out_2015, Ring_2016, Schwarz_2015). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, six classify as VUS and one classifies as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000131566	SCV002530854	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000229880	SCV004018621	uncertain significance	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
True Health Diagnostics	RCV000131566	SCV000886661	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000656752	SCV001919536	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656752	SCV001971608	likely benign	not provided		no assertion criteria provided	clinical testing