5-112839954-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000038.6(APC):​c.4360A>G​(p.Lys1454Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000474 in 1,614,122 control chromosomes in the GnomAD database, including 9 homozygotes. 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: š‘“ 0.0025 ( 5 hom., cov: 32)
Exomes š‘“: 0.00026 ( 4 hom. )

Consequence

APC
NM_000038.6 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:16

Conservation

PhyloP100: 4.04
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005815476).
BP6
Variant 5-112839954-A-G is Benign according to our data. Variant chr5-112839954-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127295.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=9, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00252 (383/152248) while in subpopulation AFR AF= 0.00888 (369/41558). AF 95% confidence interval is 0.00813. There are 5 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 383 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.4360A>G p.Lys1454Glu missense_variant Exon 16 of 16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkc.4360A>G p.Lys1454Glu missense_variant Exon 16 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+10982A>G intron_variant Intron 3 of 7 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.00246
AC:
374
AN:
152130
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00869
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000597
AC:
150
AN:
251232
Hom.:
0
AF XY:
0.000471
AC XY:
64
AN XY:
135780
show subpopulations
Gnomad AFR exome
AF:
0.00794
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000261
AC:
382
AN:
1461874
Hom.:
4
Cov.:
33
AF XY:
0.000224
AC XY:
163
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00938
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.000596
GnomAD4 genome
AF:
0.00252
AC:
383
AN:
152248
Hom.:
5
Cov.:
32
AF XY:
0.00255
AC XY:
190
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00888
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000732
Hom.:
1
Bravo
AF:
0.00294
ESP6500AA
AF:
0.00727
AC:
32
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000535
AC:
65
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:16
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:7
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 07, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 12, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency high for disorder; multiple papers question pathogenicity -

Jul 12, 2019
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 09, 2017
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 05, 2017
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

May 27, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Benign:4
Sep 19, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 06, 2024
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BA1, BP1 c.4360A>G, located in exon 16 of the APC gene, is predicted to result in the substitution of lysine by glutamic acid at codon 1454, p.(Lys1454Glu)(BP1). This variant is found in 194/23608 at a filtering allele frequency of 0.72% in the African population of the gnomAD v2.1.1 database non-cancer data set (BA1). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.554) is indeterminate regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID: 36413997). In addition, the variant was also identified in the ClinVar database (18x likely benign, 6x benign) and in LOVD database (1x uncertain significance). Based on currently available information, c.4360A>G is classified as a benign variant according to ClinGen-APC Guidelines version v1. -

Nov 25, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jan 20, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Familial adenomatous polyposis 1 Benign:2
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial multiple polyposis syndrome Uncertain:1
Oct 13, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal adenoma Uncertain:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

APC-Associated Polyposis Disorders Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial colorectal cancer Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The APC p.Lys1454Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Conflicting interpretations of pathogencitiy. Benign(6);Likely benign(4);Uncertain significance(1) ) and Cosmic (Reported x5 Confirmed somatic, identified in tumor tissue from urinary tract (x3), prostate, and haematopoetic and lymphoid tissue) databases. The variant was identified in control databases in 228 of 282622 chromosomes at a frequency of 0.0008067 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 206 of 24960 chromosomes (freq: 0.008253), Latino in 16 of 35416 chromosomes (freq: 0.000452), Other in 3 of 7214 chromosomes (freq: 0.000416), European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004), European (non-Finnish) in 2 of 128990 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys1454 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One functional study found that the p.Lys1454Glu variant suppresses beta-catenin mediated transcription at a level similar to wild-type APC in a cell culture assay, and is therefore predicted to have no effect on APC protein function (Azzopardi_2008_PMID:18199528). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not provided Benign:1
Sep 16, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The APC c.4360A>G (p.Lys1454Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant is not located in any known domain/repeat (InterPro). This variant was found in 68/123380 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0053867 (56/10396). This frequency is about 75 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In literature, the variant has also been reported in patients of various cancer phenotypes (such as FAP, prostate cancer, hepatic cancer, CRC, bladder cancer and B-cell lymphoma) including somatic occurrences, however, without strong evidence for causality. One functional study showed that this variant has a normal effect in an in vitro beta-cateninregulated transcription (CRT) assay (Azzopardi_2008). Multiple clinical labs have classified this variant as benign/likely benign (3 labs) to uncertain significance (1 lab and 1 database). Taken together, this variant has currently been classified as a Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.083
T
BayesDel_noAF
Uncertain
0.11
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;T
Eigen
Benign
-0.075
Eigen_PC
Benign
0.096
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.078
D
MetaRNN
Benign
0.0058
T;T
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
0.97
L;L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.50
N;N
REVEL
Uncertain
0.55
Sift
Benign
0.17
T;T
Sift4G
Benign
0.33
T;T
Polyphen
0.15
B;B
Vest4
0.39
MVP
0.98
ClinPred
0.031
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.56

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: rs111866410; hg19: chr5-112175651; COSMIC: COSV57320740; COSMIC: COSV57320740; API