5-112838187-C-T

Position:

chr5-112838187-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000038.6(APC):c.2593C>T(p.Pro865Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 1 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:11

Conservation

PhyloP100: 0.653

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014352292).

BP6

Variant 5-112838187-C-T is Benign according to our data. Variant chr5-112838187-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135690.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=6, Benign=2}.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.2593C>T	p.Pro865Ser	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.2593C>T	p.Pro865Ser	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.228+9215C>T		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251054

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000276

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	This variant is associated with the following publications: (PMID: 27124905, 21859464, 14695993, 31159747) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 08, 2019	- -

Familial adenomatous polyposis 1

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 03, 2022	The APC c.2593C>T (p.Pro865Ser) missense change has a maximum non-founder subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual referred for genetic testing for hereditary cancer predisposition (PMID: 31159747). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 24, 2015	- -

Familial multiple polyposis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 24, 2015

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 09, 2022

Variant summary: APC c.2593C>T (p.Pro865Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282448 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is benign. c.2593C>T has been reported in the literature in an individual with microsatellite unstable (MSI) sporadic colorectal cancer due to MLH1 promoter hypermethylation and in settings of multigene panel testing of clinical tumor samples (example, Domingo_2004, Goswami_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign/Benign, n=7; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

APC-Associated Polyposis Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.55

.;D;D;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.82

T;.;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.83

.;L;L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.36

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.41

T;T;T;T

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.067, 0.057

MVP

0.77

ClinPred

0.013

GERP RS

3.1

Varity_R

0.030

gMVP

0.40

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