Submissions for variant NM_000038.6(APC):c.7143A>C (p.Gln2381His)

gnomAD frequency: 0.00001  dbSNP: rs756153152

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003468948	SCV000260764	uncertain significance	Familial adenomatous polyposis 1	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 2381 of the APC protein (p.Gln2381His). This variant is present in population databases (rs756153152, gnomAD 0.01%). 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: 220313). 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	RCV000236701	SCV000294102	uncertain significance	not provided	2023-08-08	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)
Ambry Genetics	RCV000568621	SCV000667635	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-14	criteria provided, single submitter	clinical testing	The p.Q2381H variant (also known as c.7143A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 7143. The glutamine at codon 2381 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000236701	SCV003799912	likely benign	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468948	SCV004200154	uncertain significance	Familial adenomatous polyposis 1	2023-09-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997631	SCV004826354	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-05-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739596	SCV005364647	uncertain significance	APC-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The APC c.7143A>C variant is predicted to result in the amino acid substitution p.Gln2381His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/220313/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.