rs459552

chr5-112841059-T-Achr5-112841059-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000038.6(APC):c.5465T>A(p.Val1822Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.781 in 1,611,172 control chromosomes in the GnomAD database, including 493,662 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1822G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.82 (51880 hom., cov: 31)
  • Exomes 𝑓: 0.78 (441782 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign reviewed by expert panel B:22 O:3
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3279884E-7).
• BP6: Variant 5-112841059-T-A is Benign according to our data. Variant chr5-112841059-T-A is described in ClinVar as [Benign]. Clinvar id is 21030.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr5-112841059-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5465T>A	p.Val1822Asp	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5465T>A	p.Val1822Asp	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124670 AN: 152042 Hom.: 51821 Cov.: 31

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

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.: 53 AF XY: 0.776 AC XY: 563110 AN XY: 725998

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.: 31 AF XY: 0.816 AC XY: 60692 AN XY: 74374

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:22 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

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

Familial adenomatous polyposis 1 Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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). -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Benign:3

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, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
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	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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2015	- -
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	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	13
Dann	Benign	0.81
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.050	N
MetaRNN	Benign	6.3e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N;N
MutationTaster	Benign	0.98	P;P;P
PrimateAI	Uncertain	0.49	T
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	T
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

Other links and lift over

dbSNP: rs459552; hg19: chr5-112176756; COSMIC: COSV57321643; COSMIC: COSV57321643;