chr5-112840862-T-G

Position:

chr5-112840862-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000038.6(APC):c.5268T>G(p.Ser1756Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,613,728 control chromosomes in the GnomAD database, including 319,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28136 hom., cov: 32)

Exomes 𝑓: 0.63 ( 291657 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 0.169

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 5-112840862-T-G is Benign according to our data. Variant chr5-112840862-T-G is described in ClinVar as [Benign]. Clinvar id is 42245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112840862-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.169 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.5268T>G	p.Ser1756Ser	synonymous_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.5268T>G	p.Ser1756Ser	synonymous_variant	16/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.228+11890T>G		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91592

AN:

151940

Hom.:

28119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.535

Gnomad AMI

AF:

0.614

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.574

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.731

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.615

Gnomad OTH

AF:

0.615

GnomAD3 exomes

AF:

0.651

AC:

163104

AN:

250444

Hom.:

54120

AF XY:

0.651

AC XY:

88162

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.534

Gnomad AMR exome

AF:

0.734

Gnomad ASJ exome

AF:

0.592

Gnomad EAS exome

AF:

0.821

Gnomad SAS exome

AF:

0.714

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.621

Gnomad OTH exome

AF:

0.650

GnomAD4 exome

AF:

0.629

AC:

919568

AN:

1461670

Hom.:

291657

Cov.:

AF XY:

0.631

AC XY:

458889

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.521

Gnomad4 AMR exome

AF:

0.727

Gnomad4 ASJ exome

AF:

0.591

Gnomad4 EAS exome

AF:

0.840

Gnomad4 SAS exome

AF:

0.710

Gnomad4 FIN exome

AF:

0.574

Gnomad4 NFE exome

AF:

0.618

Gnomad4 OTH exome

AF:

0.635

GnomAD4 genome

AF:

0.603

AC:

91661

AN:

152058

Hom.:

28136

Cov.:

AF XY:

0.604

AC XY:

44907

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.535

Gnomad4 AMR

AF:

0.669

Gnomad4 ASJ

AF:

0.574

Gnomad4 EAS

AF:

0.819

Gnomad4 SAS

AF:

0.731

Gnomad4 FIN

AF:

0.536

Gnomad4 NFE

AF:

0.615

Gnomad4 OTH

AF:

0.613

Alfa

AF:

0.607

Hom.:

26750

Bravo

AF:

0.611

Asia WGS

AF:

0.755

AC:

2622

AN:

3478

EpiCase

AF:

0.612

EpiControl

AF:

0.615

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2008	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 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 28, 2016	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -

Familial adenomatous polyposis 1

Benign:2

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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.5268T>G, p.Ser1756Ser silent variant, located in exon 16 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs_id: rs866006) with a heterozygosity freqency of 0.478+/-0.104. Based on the above information, this is a benign variant. -

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

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.24

DANN

Benign

0.52

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