rs1064792980
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.4404_4418delinsC(p.Lys1468AsnfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 frameshift
NM_000038.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.96
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 316 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-112839998-GCAAGCTGCAGTAAA-C is Pathogenic according to our data. Variant chr5-112839998-GCAAGCTGCAGTAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 411550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.4404_4418delinsC | p.Lys1468AsnfsTer14 | frameshift_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.4404_4418delinsC | p.Lys1468AsnfsTer14 | frameshift_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 10, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2016 | For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in APC are known to be pathogenic (PMID: 20685668, 17963004). This sequence change deletes 18 nucleotide and inserts 1 nucleotide in exon 16 of the APC mRNA (c.4404_4418delinsC), causing a frameshift at codon 1348. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Gln1469Cysfs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein by eliminating over 1400 amino acid residues (~50%) from the full length protein. . - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at