Submissions for variant NM_000038.6(APC):c.7594C>T (p.His2532Tyr)

gnomAD frequency: 0.00004  dbSNP: rs375080917

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203815	SCV000260524	uncertain significance	Familial adenomatous polyposis 1	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 2532 of the APC protein (p.His2532Tyr). This variant is present in population databases (rs375080917, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 220176). 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.
GeneDx	RCV000587117	SCV000567815	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31784493)
Ambry Genetics	RCV000561106	SCV000667350	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The p.H2532Y variant (also known as c.7594C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 7594. The histidine at codon 2532 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587117	SCV000694121	uncertain significance	not provided	2016-06-20	criteria provided, single submitter	clinical testing	Variant summary: The APC c.7594C>T (p.His2532Tyr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/121346 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714).The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been classified as VUS by one lab in ClinVar. The variant has been reported in the germline of a sample by a lab and as somatic occurrence in one endometrial cancer by COSMIC; both without strong evidence for or against pathogenicity. Because of lack of sufficient clinical information and functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl	RCV000203815	SCV000785105	uncertain significance	Familial adenomatous polyposis 1	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561106	SCV000909632	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 2532 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 5/282074 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002346	SCV001160250	uncertain significance	not specified	2019-01-23	criteria provided, single submitter	clinical testing	The APC c.7594C>T; p.His2532Tyr variant (rs375080917), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 220176). This variant is found on only five chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 2532 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. The vast majority of pathogenic APC variants are truncating nonsense or frameshift variants. However, given the lack of clinical and functional data, the significance of the p.His2532Tyr variant is uncertain at this time. References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587117	SCV001470121	uncertain significance	not provided	2020-08-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561106	SCV002528215	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000203815	SCV004019700	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	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.
Baylor Genetics	RCV000203815	SCV004209576	uncertain significance	Familial adenomatous polyposis 1	2023-08-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997620	SCV004835701	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 2532 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 reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282074 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.