rs149154604

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000038.6(APC):c.848G>A(p.Arg283Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000041 in 1,611,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 5.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.081466794).

BP6

Variant 5-112815508-G-A is Benign according to our data. Variant chr5-112815508-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3}.

BS2

High AC in GnomAdExome4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.848G>A	p.Arg283Gln	missense_variant	9/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.848G>A	p.Arg283Gln	missense_variant	9/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251064

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1459038

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

725892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 17, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 14, 2020	Variant summary: APC c.848G>A (p.Arg283Gln) results in a 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 8.4e-05 in 251064 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), suggesting that the variant is benign. c.848G>A has been reported in the literature in individuals affected with Lynch Syndrome (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Six 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 n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2019

This variant is associated with the following publications: (PMID: 29684080, 27882345, 25980754, 25801821) -

APC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T;T;T

Eigen

Benign

-0.016

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.081

T;T;T;T

MetaSVM

Uncertain

0.040

MutationAssessor

Benign

0.86

.;L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.25

N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.67

T;T;T;T

Polyphen

0.024

.;B;B;.

Vest4

0.47, 0.39

MutPred

0.10

.;Loss of MoRF binding (P = 0.0775);Loss of MoRF binding (P = 0.0775);Loss of MoRF binding (P = 0.0775);

MVP

0.82

ClinPred

0.19

GERP RS

4.2

Varity_R

0.12

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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