rs147549623

Positions:

chr5-112843108-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000038.6(APC):c.7514G>A(p.Arg2505Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,984 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 6 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 2.99

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:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12488851).

BP6

Variant 5-112843108-G-A is Benign according to our data. Variant chr5-112843108-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112843108-G-A is described in Lovd as [Likely_benign]. Variant chr5-112843108-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00131 (1917/1461732) while in subpopulation NFE AF= 0.0016 (1784/1111886). AF 95% confidence interval is 0.00154. There are 6 homozygotes in gnomad4_exome. There are 944 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.7514G>A	p.Arg2505Gln	missense_variant	16/16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.7514G>A	p.Arg2505Gln	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.229-13541G>A		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000824

AC:

207

AN:

251232

Hom.:

AF XY:

0.000877

AC XY:

119

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00131

AC:

1917

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

944

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00160

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000939

AC:

143

AN:

152252

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000790

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000815

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:12

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2016	Variant summary: The APC c.7514G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to Gln. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 102/125206 control chromosomes (1 homozygote) at a frequency of 0.0008147, which is about 14 times the maximal expected frequency of a pathogenic APC allele (0.0000602), suggesting this variant is benign. Thie variant has been reported in patients with MAP/FAP, CRC or pancreatic cancer. In one CRC family, this variant did not co-segregate with the disease (Zhou_2004), highly suggesting this variant is not causative. In addition, multiple clinical laboratories classified this variant as benign/likely benign. Taken together, this variant was classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 01, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Arg2505Gln variant was identified in 4 of 2376 proband chromosomes (frequency: 0.002) from individuals with colorectal adenomas or colorectal cancer (Azzopardi 2008, Lefevre 2012, Zhou 2004) and was present in 2 of 3862 control chromosomes (frequency: 0.001). The variant was also listed at a frequency of 0.001 in the â€šÃ„ÃºNHLBI Exome Sequencing Projectâ€šÃ„Ã¹, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In a study by Zhou (2004), the variant was found incidentally in two members of a family with hereditary colorectal cancer but did not segregate with disease in other affected family members. The variant was listed in dbSNP (ID: rs147549623) and the â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, but was not identified in other databases searched, including HGMD, UMD and COSMIC. The p.Arg2505 residue is conserved in mammals and lower organisms; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact of the variant amino acid to the protein and this information is not very predictive of pathogenicity. Additional study is needed to determine the clinical significance of this variant. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	APC: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 20, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 31, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 31, 2018	This alteration is classified as likely 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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 16, 2024	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2018	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial adenomatous polyposis 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 09, 2024	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Classic or attenuated familial adenomatous polyposis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.37

PROVEAN

Benign

0.070

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.23

T;T

Sift4G

Benign

0.17

T;T

Polyphen

1.0

D;D

Vest4

0.59

MVP

0.84

ClinPred

0.057

GERP RS

6.0

Varity_R

0.094

gMVP

0.59

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