5-112837856-T-G

Position:

chr5-112837856-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000038.6(APC):c.2262T>G(p.Val754Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.777

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 5-112837856-T-G is Benign according to our data. Variant chr5-112837856-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 135687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.777 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000913 (139/152274) while in subpopulation AFR AF= 0.00315 (131/41542). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.2262T>G	p.Val754Val	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.2262T>G	p.Val754Val	synonymous_variant	16/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.228+8884T>G		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000315

AC:

AN:

250416

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000913

AC:

139

AN:

152274

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000377

Hom.:

Bravo

AF:

0.00108

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2017	Variant summary: The APC c.2262T>G (p.Val754Val) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create ESE binding sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 102/276142 control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.003833 (92/24002). This frequency is about 54 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), strongly suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign or benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 14, 2019	- -

Familial adenomatous polyposis 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 21, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 09, 2014	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 02, 2017

- -

Classic or attenuated familial adenomatous polyposis

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.6

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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