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rs1064794163

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000038.6(APC):c.1409-2A>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

APC
NM_000038.6 splice_acceptor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.30
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 Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.016291607 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.3, offset of -36, new splice context is: accagtttgttttattttAGatg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 5-112827106-A-C is Pathogenic according to our data. Variant chr5-112827106-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112827106-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APCNM_000038.6 linkuse as main transcriptc.1409-2A>C splice_acceptor_variant ENST00000257430.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.1409-2A>C splice_acceptor_variant 5 NM_000038.6 P1P25054-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 21, 2022This sequence change affects an acceptor splice site in intron 11 of the APC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). ClinVar contains an entry for this variant (Variation ID: 419874). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 9950360, 19036155; Invitae). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.May 01, 2023This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. Functional studies indicate this variant impacts protein function [PMID: 15459959]. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 21, 2015This pathogenic variant is denoted APC c.1409-2A>C or IVS11-2A>C and consists of an A>C nucleotide substitution at the -2 position of intron 11 of the APC gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in association with familial adenomatous polyposis (FAP) (Aretz 2004) and we consider it to be pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 05, 2021This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. Found in at least one patient with expected phenotype for this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 30, 2019The c.1409-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 11 in the APC gene. This mutation was identified in 1/1164 unrelated German index patients with a clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (Aretz S et al. Hum. Mutat., 2004 Nov;24:370-80; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114). A different mutation at the same nucleotide position, c.1409-2A>G, was detected in an AFAP patient and demonstrated aberrant splicing (Aretz S et al. Hum. Mutat., 2004 Nov;24:370-80). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.30
Cadd
Pathogenic
36
Dann
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D;D
GERP RS
5.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.96
Position offset: 13
DS_AL_spliceai
1.0
Position offset: 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: rs1064794163; hg19: chr5-112162803; API