rs587782886

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_000038.6(APC):​c.1139G>A​(p.Arg380Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 10.0
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.781
BP6
Variant 5-112819171-G-A is Benign according to our data. Variant chr5-112819171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143004.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APCNM_000038.6 linkuse as main transcriptc.1139G>A p.Arg380Gln missense_variant 10/16 ENST00000257430.9 NP_000029.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.1139G>A p.Arg380Gln missense_variant 10/165 NM_000038.6 ENSP00000257430 P1P25054-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000838
AC:
21
AN:
250708
Hom.:
0
AF XY:
0.0000812
AC XY:
11
AN XY:
135482
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000547
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000795
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000965
AC:
141
AN:
1461688
Hom.:
0
Cov.:
33
AF XY:
0.0000908
AC XY:
66
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000106
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000650
Hom.:
0
Bravo
AF:
0.0000642
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 29, 2024This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submittercurationSema4, Sema4Dec 28, 2020- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2018This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 03, 2022- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 30, 2022Variant summary: APC c.1139G>A (p.Arg380Gln) results in a conservative amino acid change located in the Armadillo repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250708 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4.0 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 a benign polymorphism found primarily in populations of Latino origin. c.1139G>A has been reported in the literature in settings of multigene panel testing among individuals affected with Familial Adenomatous Polyposis/colorectal cancer (example, Kerr_2013, Hansen_2017, Castellanos_2017). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign (n=5) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 21, 2020- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 08, 2021This variant is associated with the following publications: (PMID: 28195393, 23159591, 28051113) -
APC-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 26, 2023This 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
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
.;D;D;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;.;D;D
M_CAP
Benign
0.075
D
MetaRNN
Pathogenic
0.78
D;D;D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
2.9
.;M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.7
D;D;D;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.013
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.90, 0.73
MutPred
0.34
.;Gain of ubiquitination at K377 (P = 0.0328);Gain of ubiquitination at K377 (P = 0.0328);Gain of ubiquitination at K377 (P = 0.0328);
MVP
0.94
ClinPred
0.94
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.89
gMVP
0.73

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.

Other links and lift over

dbSNP: rs587782886; hg19: chr5-112154868; API