chr5-112842051-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000038.6(APC):c.6457G>T(p.Asp2153Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2153N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.15

Publications

0 publications found

Variant links:

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]

APC Gene-Disease associations (from GenCC):

classic or attenuated familial adenomatous polyposis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
desmoid tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
familial adenomatous polyposis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
gastric adenocarcinoma and proximal polyposis of the stomach
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
APC-related attenuated familial adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Turcot syndrome with polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.6457G>T	p.Asp2153Tyr	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 link	c.6457G>T	p.Asp2153Tyr	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+13079G>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250094

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111214

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:1

Feb 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 2153 of the APC protein (p.Asp2153Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant has not been reported in the literature in individuals with APC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

not provided

Uncertain:1

Mar 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.089

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.81

L;L

PhyloP100

7.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

1.0

D;D

Vest4

0.74

MutPred

0.20

Gain of phosphorylation at D2153 (P = 0.0195);Gain of phosphorylation at D2153 (P = 0.0195);

MVP

0.98

ClinPred

0.70

GERP RS

6.0

Varity_R

0.23

gMVP

0.51

Mutation Taster

=21/79

disease causing

(source)

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

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chr5-112842051-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over