chr5-112842754-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000038.6(APC):ā€‹c.7160A>Gā€‹(p.Asn2387Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.09
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08697045).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APCNM_000038.6 linkuse as main transcriptc.7160A>G p.Asn2387Ser missense_variant 16/16 ENST00000257430.9 NP_000029.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.7160A>G p.Asn2387Ser missense_variant 16/165 NM_000038.6 ENSP00000257430 P1P25054-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461676
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 20, 2023The p.N2387S variant (also known as c.7160A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 7160. The asparagine at codon 2387 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported as VUS in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration was also detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 03, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingGeneKor MSAAug 01, 2018- -
Familial adenomatous polyposis 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsFeb 12, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 04, 2022This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2387 of the APC protein (p.Asn2387Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 490355). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 16, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
13
DANN
Benign
0.84
DEOGEN2
Benign
0.27
T;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.068
FATHMM_MKL
Benign
0.60
D
LIST_S2
Uncertain
0.91
.;D
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.087
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
-0.92
N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.45
N;N
REVEL
Benign
0.18
Sift
Benign
0.86
T;T
Sift4G
Benign
0.95
T;T
Polyphen
0.0
B;B
Vest4
0.082
MutPred
0.36
Gain of phosphorylation at N2387 (P = 0.0247);Gain of phosphorylation at N2387 (P = 0.0247);
MVP
0.67
ClinPred
0.43
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.036
gMVP
0.14

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: rs1554088085; hg19: chr5-112178451; API