Submissions for variant NM_000038.6(APC):c.3426T>A (p.Asn1142Lys)

gnomAD frequency: 0.00001  dbSNP: rs375478525

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130415	SCV000185277	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-24	criteria provided, single submitter	clinical testing	The p.N1142K variant (also known as c.3426T>A), located in coding exon 15 of the APC gene, results from a T to A substitution at nucleotide position 3426. The asparagine at codon 1142 is replaced by lysine, an amino acid with similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000235983	SCV000292455	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3426T>A at the cDNA level, p.Asn1142Lys (N1142K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn1142Lys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asn1142Lys occurs at a position that is conserved across species and is located in a Beta-catenin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Asn1142Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130415	SCV000681599	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1142 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250980 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.
Invitae	RCV003650395	SCV000953844	uncertain significance	Familial adenomatous polyposis 1	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1142 of the APC protein (p.Asn1142Lys). This variant is present in population databases (rs375478525, gnomAD 0.003%). 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: 141774). 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235983	SCV001470102	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing