Submissions for variant NM_000038.6(APC):c.4440G>C (p.Gln1480His)

dbSNP: rs876659881

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564996	SCV000667597	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	The p.Q1480H variant (also known as c.4440G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 4440. The glutamine at codon 1480 is replaced by histidine, an amino acid with highly 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002528059	SCV000830710	uncertain significance	Familial adenomatous polyposis 1	2024-12-30	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 1480 of the APC protein (p.Gln1480His). 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: 482375). 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.
Color Diagnostics, LLC DBA Color Health	RCV000564996	SCV001342183	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 1480 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 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268184	SCV002550624	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV003222044	SCV003918386	uncertain significance	not provided	2022-10-17	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, 27533247)
Baylor Genetics	RCV002528059	SCV004206638	uncertain significance	Familial adenomatous polyposis 1	2023-05-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000980	SCV004837934	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 1480 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 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002528059	SCV005402162	uncertain significance	Familial adenomatous polyposis 1	2024-01-22	criteria provided, single submitter	clinical testing	The APC c.4440G>C (p.Gln1480His) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with APC-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.?
3DMed Clinical Laboratory Inc	RCV000677759	SCV000803915	uncertain significance	Intrahepatic cholangiocarcinoma	2017-08-16	no assertion criteria provided	clinical testing