5-112834953-A-T

Variant names:

• chr5-112834953-A-T
• rs876658969
• NM_000038.6:c.1746A>T

Variant summary

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

The NM_000038.6(APC):​c.1746A>T​(p.Glu582Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1746A>T	p.Glu582Asp	missense_variant, splice_region_variant	Exon 15 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1746A>T	p.Glu582Asp	missense_variant, splice_region_variant	Exon 15 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+5981A>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 05, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E582D variant (also known as c.1746A>T), located in coding exon 14 of the APC gene, results from an A to T substitution at nucleotide position 1746. The glutamic acid at codon 582 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;D;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Uncertain	2.4	.;M;M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D;D;D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.023	D;D;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		0.99	.;D;D;.;.
Vest4		0.69, 0.70
MutPred		0.43		.;Loss of methylation at K580 (P = 0.1112);Loss of methylation at K580 (P = 0.1112);Loss of methylation at K580 (P = 0.1112);.;
MVP		0.73
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.71
gMVP		0.62

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: rs876658969; hg19: chr5-112170650;