rs1057517544
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.5952_5955del(p.Glu1985LeufsTer58) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N1984N) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 frameshift
NM_000038.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.31
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 138 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-112841543-AAATG-A is Pathogenic according to our data. Variant chr5-112841543-AAATG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112841543-AAATG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.5952_5955del | p.Glu1985LeufsTer58 | frameshift_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5952_5955del | p.Glu1985LeufsTer58 | 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/Likely pathogenic
Submissions summary: Pathogenic:3
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 | Invitae | Feb 22, 2019 | For these reasons, this variant has been classified as Pathogenic. This variant removes the Basic Domain, the EB1 Binding Site, and the HDLG Binding Site of the APC protein, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect of this variant on APC protein function, a different truncating variant, c.7932_7935del (p.Tyr2645Lysfs*14), that only removes the EB1 and HDLG binding sites has been reported in several individuals with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1316610, 8381579, 9824584, 22135120). These observations suggest that the C-terminal portion of the protein is clinically important. This variant has been reported in the literature in an individual suspected of familial adenomatous polyposis (FAP) (PMID: 20223039). This variant is not present in population databases (ExAC no frequency). This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.5952_5955delTGAA), causing a frameshift at codon 1985. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Glu1985Leufs*58). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 30, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2021 | The c.5952_5955delTGAA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides between positions 5952 and 5955, causing a translational frameshift with a predicted alternate stop codon (p.E1985Lfs*58). This alteration occurs at the 3' terminus of APC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 30% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in one German polyposis patient (Friedl W and Aretz S Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at