5-112844036-G-C

Position:

• chr5-112844036-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000038.6(APC):​c.8442G>C​(p.Lys2814Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.67

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.8442G>C	p.Lys2814Asn	missense_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.8442G>C	p.Lys2814Asn	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.229-12613G>C		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2020

In summary, this variant has uncertain impact on APC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with an APC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 2814 of the APC protein (p.Lys2814Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2023

The p.K2814N variant (also known as c.8442G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 8442. The lysine at codon 2814 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.95	N;N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.044	D;D
Polyphen		1.0	D;D
Vest4		0.58
MutPred		0.43		Loss of methylation at K2814 (P = 0.002);Loss of methylation at K2814 (P = 0.002);
MVP		0.81
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1267993620; hg19: chr5-112179733;