Submissions for variant NM_000038.6(APC):c.4310A>G (p.Lys1437Arg)

gnomAD frequency: 0.00002  dbSNP: rs745825088

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220589	SCV000274364	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-25	criteria provided, single submitter	clinical testing	The p.K1437R variant (also known as c.4310A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4310. The lysine at codon 1437 is replaced by arginine, an amino acid with highly similar properties. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). 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 variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463670	SCV000552570	uncertain significance	Familial adenomatous polyposis 1	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1437 of the APC protein (p.Lys1437Arg). This variant is present in population databases (rs745825088, gnomAD 0.004%). 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: 230719). 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.
Mendelics	RCV000463670	SCV000838114	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220589	SCV000911517	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-07	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1437 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 been identified in 4/251050 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.
GeneDx	RCV001785522	SCV002028261	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Not observed at a 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)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001785522	SCV002046429	uncertain significance	not provided	2022-12-03	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000026 (3/113452 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320610	SCV004025060	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000463670	SCV004195122	uncertain significance	Familial adenomatous polyposis 1	2024-01-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997856	SCV004837907	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1437 of the APC protein. Computational prediction tool 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). 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 been identified in 4/251050 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.