Submissions for variant NM_000038.6(APC):c.5302A>G (p.Lys1768Glu)

gnomAD frequency: 0.00001  dbSNP: rs199630012

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766438	SCV000149011	uncertain significance	not provided	2017-04-11	criteria provided, single submitter	clinical testing	This variant is denoted APC c.5302A>G at the cDNA level, p.Lys1768Glu (K1768E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. APC Lys1768Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Lys1768Glu occurs at a position that is not conserved and is located in the 20-amino acid repeat beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Lys1768Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115102	SCV000186217	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.K1768E variant (also known as c.5302A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5302. The lysine at codon 1768 is replaced by glutamic acid, 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 not well 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.
Counsyl	RCV000411965	SCV000489362	uncertain significance	Familial adenomatous polyposis 1	2016-09-27	criteria provided, single submitter	clinical testing
Invitae	RCV003743564	SCV000647573	uncertain significance	Familial adenomatous polyposis 1	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1768 of the APC protein (p.Lys1768Glu). This variant is present in population databases (rs199630012, 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: 127304). 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.
Color Diagnostics, LLC DBA Color Health	RCV000115102	SCV000687013	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1768 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 APC-related disorders in the literature. This variant has been identified in 3/250580 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766438	SCV001469313	uncertain significance	not provided	2019-09-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315630	SCV004018806	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
CeGaT Center for Human Genetics Tuebingen	RCV000766438	SCV004032617	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	APC: PM2, BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000766438	SCV000591190	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Lys1768Glu variant was not identified in the literature, nor was it identified in the HGMD, UMD, “InSiGHT Colon Cancer Database”, or the COSMIC database. The variant was listed in dbSNP (ID: rs199630012) and was identified in the NHLBI Exome Sequencing Project (Exome Variant Server) in 2 of 8598 European American alleles; though the low number and frequency of this variant is not substantive enough to determine the prevalence of this variant in the general population. The p.Lys1768 residue is conserved in most mammals, suggesting that this may be an important residue; however, the variant amino acid glutamic acid (Glu) is present in platypus, chicken, and zebrafish, increasing the likelihood that this variant may not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. One study suggests that this residue is part of one APC nuclear localization signal located from residues 1767-1772, and a substitution of alanine residues for lysine residues at positions 1768-1771 was shown to abolish nuclear localization signal activity (Zhang 2000). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.