Submissions for variant NM_000038.6(APC):c.7573C>T (p.Arg2525Cys)

gnomAD frequency: 0.00001  dbSNP: rs774952444

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202809	SCV000257789	uncertain significance	Familial multiple polyposis syndrome	2015-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000590375	SCV000292465	uncertain significance	not provided	2024-04-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25801821, 32277576, 29684080, 25559809, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517343	SCV000552520	uncertain significance	Familial adenomatous polyposis 1	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2525 of the APC protein (p.Arg2525Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with biliary tract cancer and/or colorectal cancer (PMID: 25559809, 36243179). ClinVar contains an entry for this variant (Variation ID: 218507). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236933	SCV000600153	uncertain significance	not specified	2017-06-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573374	SCV000667438	benign	Hereditary cancer-predisposing syndrome	2024-10-01	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000573374	SCV000681877	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2525 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 25559809). This variant has been identified in 13/250824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590375	SCV000694120	uncertain significance	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236933	SCV002760367	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000590375	SCV003826844	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002517343	SCV004197642	uncertain significance	Familial adenomatous polyposis 1	2024-03-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997051	SCV004835695	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2525 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 25559809), an individual affected with breast cancer (PMID: 29684080), and in individuals affected with pancreatic cancer (PMID: 32980694). This variant has been identified in 13/250824 chromosomes in the general population by the Genome Aggregation Database (gnomAD), and in healthy control individuals (PMID: 32980694). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000573374	SCV005045357	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing