Submissions for variant NM_000038.6(APC):c.5533C>T (p.His1845Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1060503338

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526455	SCV000552688	uncertain significance	Familial adenomatous polyposis 1	2025-01-29	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 1845 of the APC protein (p.His1845Tyr). This variant is not present in population databases (gnomAD no frequency). 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: 411499). 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.
Ambry Genetics	RCV001024240	SCV001186222	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-03	criteria provided, single submitter	clinical testing	The p.H1845Y variant (also known as c.5533C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 5533. The histidine at codon 1845 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001024240	SCV001347269	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1845 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 not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283865	SCV001469314	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001283865	SCV002004118	uncertain significance	not provided	2024-02-20	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: 18199528)
Baylor Genetics	RCV002526455	SCV004198890	uncertain significance	Familial adenomatous polyposis 1	2023-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001963	SCV004838068	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1845 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.