rs459552

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.5465T>A	p.Val1822Asp	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 linkuse as main transcript	c.5465T>A	p.Val1822Asp	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

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

GnomAD3 exomes

AF:

0.795

AC:

199083

AN:

250474

Hom.:

79771

AF XY:

0.789

AC XY:

106909

AN XY:

135464

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 SAS exome

AF:

0.782

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

Gnomad4 AFR exome

AF:

0.961

Gnomad4 AMR exome

AF:

0.827

Gnomad4 ASJ exome

AF:

0.766

Gnomad4 EAS exome

AF:

0.904

Gnomad4 SAS exome

AF:

0.779

Gnomad4 FIN exome

AF:

0.695

Gnomad4 NFE exome

AF:

0.768

Gnomad4 OTH exome

AF:

0.789

GnomAD4 genome

AF:

0.820

AC:

124789

AN:

152160

Hom.:

51880

Cov.:

AF XY:

0.816

AC XY:

60692

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.957

Gnomad4 AMR

AF:

0.812

Gnomad4 ASJ

AF:

0.761

Gnomad4 EAS

AF:

0.902

Gnomad4 SAS

AF:

0.793

Gnomad4 FIN

AF:

0.669

Gnomad4 NFE

AF:

0.761

Gnomad4 OTH

AF:

0.815

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2008	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial adenomatous polyposis 1

Benign:5Other:1

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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. -
Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	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

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327, 27347161, 27153395, 9950360, 18343606, 20027139, 21859464, 24599579, 21995949, 20510605, 20149637, 16569251, 16574953, 22703879) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -

Familial multiple polyposis syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Familial colorectal cancer

Other:1

other, no assertion criteria provided

literature only

Systems Biology Platform Zhejiang California International NanoSystems Institute

- -

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

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

MutationTaster

Benign

0.98

P;P;P

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over