Submissions for variant NM_000038.6(APC):c.3964G>A (p.Glu1322Lys)

gnomAD frequency: 0.00001  dbSNP: rs752926571

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219449	SCV000276920	likely benign	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004563195	SCV000552745	uncertain significance	Familial adenomatous polyposis 1	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1322 of the APC protein (p.Glu1322Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 232718). 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	RCV000485020	SCV000569018	uncertain significance	not provided	2024-01-23	criteria provided, single submitter	clinical testing	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)
Color Diagnostics, LLC DBA Color Health	RCV000219449	SCV000909266	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1322 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 been reported in an individual affected with advanced cancer (PMID: 28873162). This variant has been identified in 7/282580 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.
Genetic Services Laboratory, University of Chicago	RCV001818536	SCV002066754	uncertain significance	not specified	2021-01-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.3964G>A, in exon 16 that results in an amino acid change, p.Glu1322Lys. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database in seven individuals with an overall population frequency of 0.003% (dbSNP rs752926571). The p.Glu1322Lys change affects a highly conserved amino acid residue located in a domain of the APC protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu1322Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu1322Lys change remains unknown at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485020	SCV004219338	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	The APC c.3964G>A (p.Glu1322Lys) variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000085 (3/35426 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997998	SCV004837858	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1322 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 been reported in an individual affected with advanced cancer (PMID: 28873162). This variant has been identified in 7/282580 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.
Baylor Genetics	RCV004563195	SCV005052099	uncertain significance	Familial adenomatous polyposis 1	2024-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031799	SCV005667849	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739616	SCV005358518	uncertain significance	APC-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The APC c.3964G>A variant is predicted to result in the amino acid substitution p.Glu1322Lys. This variant has been reported as a variant of uncertain significance in an individual affected with advanced cancer (Mandelker D. et al. 2017. PubMed ID: 28873162). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD and has been interpreted as a variant of uncertain significance and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/232718/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.