rs459552

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP1

This summary comes from the ClinGen Evidence Repository: The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010422/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.82 ( 51880 hom., cov: 31)

Exomes 𝑓: 0.78 ( 441782 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:22O:3

Conservation

PhyloP100: 2.36

Publications

190 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: Benign. The variant received -9 ACMG points.

BP1

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.5465T>A	p.Val1822Asp	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.5465T>A	p.Val1822Asp	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+12087T>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.820

AC:

124670

AN:

152042

Hom.:

51821

Cov.:

show subpopulations

Gnomad AFR

AF:

0.956

Gnomad AMI

AF:

0.782

Gnomad AMR

AF:

0.812

Gnomad ASJ

AF:

0.761

Gnomad EAS

AF:

0.902

Gnomad SAS

AF:

0.793

Gnomad FIN

AF:

0.669

Gnomad MID

AF:

0.813

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.816

GnomAD2 exomes

AF:

0.795

AC:

199083

AN:

250474

AF XY:

0.789

show subpopulations

Gnomad AFR exome

AF:

0.959

Gnomad AMR exome

AF:

0.827

Gnomad ASJ exome

AF:

0.766

Gnomad EAS exome

AF:

0.903

Gnomad FIN exome

AF:

0.688

Gnomad NFE exome

AF:

0.771

Gnomad OTH exome

AF:

0.792

GnomAD4 exome

AF:

0.777

AC:

1133202

AN:

1459012

Hom.:

441782

Cov.:

AF XY:

0.776

AC XY:

563110

AN XY:

725998

show subpopulations

African (AFR)

AF:

0.961

AC:

32111

AN:

33408

American (AMR)

AF:

0.827

AC:

36984

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.766

AC:

20005

AN:

26112

East Asian (EAS)

AF:

0.904

AC:

35881

AN:

39672

South Asian (SAS)

AF:

0.779

AC:

67182

AN:

86204

European-Finnish (FIN)

AF:

0.695

AC:

37090

AN:

53394

Middle Eastern (MID)

AF:

0.788

AC:

4543

AN:

5764

European-Non Finnish (NFE)

AF:

0.768

AC:

851815

AN:

1109448

Other (OTH)

AF:

0.789

AC:

47591

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14897

29794

44692

59589

74486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20486

40972

61458

81944

102430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.820

AC:

124789

AN:

152160

Hom.:

51880

Cov.:

AF XY:

0.816

AC XY:

60692

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.957

AC:

39732

AN:

41534

American (AMR)

AF:

0.812

AC:

12422

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.761

AC:

2640

AN:

3468

East Asian (EAS)

AF:

0.902

AC:

4677

AN:

5184

South Asian (SAS)

AF:

0.793

AC:

3823

AN:

4818

European-Finnish (FIN)

AF:

0.669

AC:

7073

AN:

10572

Middle Eastern (MID)

AF:

0.823

AC:

242

AN:

294

European-Non Finnish (NFE)

AF:

0.761

AC:

51747

AN:

67970

Other (OTH)

AF:

0.815

AC:

1720

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1087

2174

3260

4347

5434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

872

1744

2616

3488

4360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.779

Hom.:

28582

Bravo

AF:

0.841

TwinsUK

AF:

0.759

AC:

2814

ALSPAC

AF:

0.778

AC:

3000

ESP6500AA

AF:

0.946

AC:

4164

ESP6500EA

AF:

0.765

AC:

6579

ExAC

AF:

0.798

AC:

96838

Asia WGS

AF:

0.856

AC:

2975

AN:

3478

EpiCase

AF:

0.764

EpiControl

AF:

0.775

ClinVar

Significance: Benign

Submissions summary: Benign:22Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Mar 01, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial adenomatous polyposis 1

Benign:5Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 24, 2014

Pathway Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Benign for Familial adenomatous polyposis 1. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Feb 26, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). -

not provided

Benign:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 27347161, 27153395, 9950360, 18343606, 20027139, 21859464, 24599579, 21995949, 20510605, 20149637, 16569251, 16574953, 22703879) -

Hereditary cancer-predisposing syndrome

Benign:3

Dec 21, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 13, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 27, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial multiple polyposis syndrome

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This p.Val1822Asp variant is not expected to have clinical significance because this residue is not conserved and the variant amino acid (Asp) is present in other mammals such as chimp, macaque, rat and dog as well as some lower evolutionary species, increasing the likelihood that this is a benign variant. In addition, it is not located near a splice junction, and is listed in dbSNP (id:rs459552) with a minor allele frequency of 0.140 in a Caucasian population. The clinical relevance of this variant is still under debate, since some studies showed that it could act as a low-penetrance allele that increases the risk of developing colorectal cancer (CRC) while others consider it as a common polymorphism without clinical consequences (Picelli_2010_20149637). In summary, based on the above information, the p.Val1822Asp variant is predicted to be benign, but we cannot rule out the possibility that this may be a low-penetrance polymorphic allele that increases risk of CRC. -

APC-Associated Polyposis Disorders

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Classic or attenuated familial adenomatous polyposis

Benign:1

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial colorectal cancer

Other:1

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.11

.;T

MetaRNN

Benign

6.3e-7

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.90

N;N

PhyloP100

2.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.59

N;N

REVEL

Benign

0.19

Sift

Benign

0.67

T;T

Sift4G

Benign

0.082

T;T

Polyphen

0.0

B;B

Vest4

0.031

ClinPred

0.0020

GERP RS

3.6

Varity_R

0.084

gMVP

0.28

Mutation Taster

=98/2

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over