5-112819332-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000038.6(APC):​c.1300G>T​(p.Asp434Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.1300G>T p.Asp434Tyr missense_variant Exon 10 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.1300G>T p.Asp434Tyr missense_variant Exon 10 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250784
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135542
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461722
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1
Aug 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 434 of the APC protein (p.Asp434Tyr). This variant is present in population databases (rs769365014, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
.;D;D;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D;.;D;D
M_CAP
Benign
0.080
D
MetaRNN
Uncertain
0.74
D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Benign
1.2
.;L;L;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.6
D;D;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D
Polyphen
0.98
.;D;D;.
Vest4
0.69, 0.73
MutPred
0.42
.;Gain of phosphorylation at D434 (P = 0.0078);Gain of phosphorylation at D434 (P = 0.0078);Gain of phosphorylation at D434 (P = 0.0078);
MVP
0.98
ClinPred
0.84
D
GERP RS
5.8
Varity_R
0.85
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs769365014; hg19: chr5-112155029; API