rs2229995

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000038.6(APC):c.7504G>A(p.Gly2502Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0199 in 1,613,962 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2502G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 40 hom., cov: 32)

Exomes 𝑓: 0.020 ( 372 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23O:1

Conservation

PhyloP100: 4.02

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006817907).

BP6

Variant 5-112843098-G-A is Benign according to our data. Variant chr5-112843098-G-A is described in ClinVar as [Benign]. Clinvar id is 41514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112843098-G-A is described in Lovd as [Benign]. Variant chr5-112843098-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.017 (2589/152258) while in subpopulation SAS AF= 0.0246 (119/4828). AF 95% confidence interval is 0.0217. There are 40 homozygotes in gnomad4. There are 1335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2589 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6 linkuse as main transcript	c.7504G>A	p.Gly2502Ser	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.7504G>A	p.Gly2502Ser	missense_variant	16/16	5	NM_000038.6	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2589

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0244

Gnomad FIN

AF:

0.0402

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.0138

GnomAD3 exomes

AF:

0.0197

AC:

4951

AN:

251266

Hom.:

AF XY:

0.0206

AC XY:

2791

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.00793

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0272

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0203

AC:

29606

AN:

1461704

Hom.:

372

Cov.:

AF XY:

0.0205

AC XY:

14934

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00272

Gnomad4 AMR exome

AF:

0.00836

Gnomad4 ASJ exome

AF:

0.0104

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0265

Gnomad4 FIN exome

AF:

0.0393

Gnomad4 NFE exome

AF:

0.0208

Gnomad4 OTH exome

AF:

0.0205

GnomAD4 genome

AF:

0.0170

AC:

2589

AN:

152258

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1335

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00428

Gnomad4 AMR

AF:

0.0150

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0246

Gnomad4 FIN

AF:

0.0402

Gnomad4 NFE

AF:

0.0227

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0137

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0198

AC:

2410

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0204

EpiControl

AF:

0.0206

ClinVar

Significance: Benign

Submissions summary: Benign:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2012	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 08, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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	curation	Sema4, Sema4	Mar 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 10, 2017	- -

Familial adenomatous polyposis 1

Benign:3

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	clinical testing	Myriad Genetics, Inc.	Apr 10, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	APC: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Familial multiple polyposis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Aug 07, 2015

- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Gly2502Ser variant was previously identified in the literature in 138 of 6866 proband chromosomes (frequency 0.020) from individuals with adenoma or colorectal cancer and in 157 of 8192 control chromosomes (frequency 0.019) from healthy individuals (Cleary 2008, Hadjisavvas 2006, Miyoshi 1992, Scott 2004, Tranah 2005, Wong 2010, Zhou 2004). This variant was also identified in the dbSNP (ID#rs2229995), HGMD, and LOVD databases, and was reported in several populations including the ESP Project with a frequency of 0.020 in European American alleles, the 1000 Genomes Project with a frequency of 0.010, and HapMap-CEU with a frequency of 0.032. The p.Gly2502 residue is not conserved through evolution and the variant (Ser) is found at this position in chicken and fruitfly, increasing the likelihood that this is a benign variant. In addition, Tranah (2005) found that this variant was not associated with risk of colorectal cancer or adenoma in men and women, and Zhou (2004) did not observe segregation of this variant with disease. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.042

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.83

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.29

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

0.030

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.30

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.15

B;B

Vest4

0.12

ClinPred

0.0096

GERP RS

6.0

Varity_R

0.060

gMVP

0.36

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