Submissions for variant NM_000038.6(APC):c.7596T>G (p.His2532Gln)

dbSNP: rs730881266

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159577	SCV000209553	uncertain significance	not provided	2017-08-29	criteria provided, single submitter	clinical testing	This variant is denoted APC c.7596T>G at the cDNA level, p.His2532Gln (H2532Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAT>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC His2532Gln was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC His2532Gln occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC His2532Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004562330	SCV001413621	uncertain significance	Familial adenomatous polyposis 1	2023-09-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 181825). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs730881266, gnomAD 0.0009%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2532 of the APC protein (p.His2532Gln).
Ambry Genetics	RCV002390386	SCV002674321	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	clinical testing	The p.H2532Q variant (also known as c.7596T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 7596. The histidine at codon 2532 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. 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.