rs1554084288

Variant names:

• chr5-112838181-T-A
• rs1554084288
• NM_000038.6:c.2587T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112838181-T-A
• chr5-112838181-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000038.6(APC):​c.2587T>A​(p.Tyr863Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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, single submitter U:1
• Conservation: PhyloP100: 6.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29680175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.2587T>A	p.Tyr863Asn	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.2587T>A	p.Tyr863Asn	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+9209T>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Jun 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces tyrosine with asparagine at codon 863 of the APC protein (p.Tyr863Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Uncertain	0.56	.;D;D;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.9	.;M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.28	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.92	.;P;P;.
Vest4		0.66, 0.85
MutPred		0.15		.;Loss of phosphorylation at Y863 (P = 0.0355);Loss of phosphorylation at Y863 (P = 0.0355);Loss of phosphorylation at Y863 (P = 0.0355);
MVP		0.87
ClinPred		0.64	D
GERP RS		6.0
Varity_R		0.079
gMVP		0.37

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: rs1554084288; hg19: chr5-112173878;