ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs774952444
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Total submissions: 10
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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 2023-09-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon or breast cancer (Chubb et al., 2015; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 25559809, 25801821, 32277576, 29684080)
Invitae RCV003534490 SCV000552520 uncertain significance Familial adenomatous polyposis 1 2024-01-24 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-14 criteria provided, single submitter clinical testing The p.R2525C variant (also known as c.7573C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 7573. The arginine at codon 2525 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in 1/626 early-onset familial colorectal cancer cases ascertained through a population-based registry in the United Kingdom (Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000573374 SCV000681877 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-04 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 uncertain significance not specified 2023-08-15 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 2023-10-26 criteria provided, single submitter clinical testing

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