rs1554088762
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000038.6(APC):c.7932_7935delTTAT(p.Tyr2645LysfsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000038.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.7932_7935delTTAT | p.Tyr2645LysfsTer14 | frameshift_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.229-13123_229-13120delTTAT | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
This sequence change results in a premature translational stop signal in the APC gene (p.Tyr2645Lysfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 199 amino acids of the APC protein. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. This variant has been observed in individuals affected with familial adenomatous polyposis (FAP) and attenuated FAP with or without extra-colonic phenotypes (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This variant is also known as Ile2644fs*7 in the literature. ClinVar contains an entry for this variant (Variation ID: 486770). -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.7932_7935delTTAT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 7932 to 7935, causing a translational frameshift with a predicted alternate stop codon (p.Y2645Kfs*14). Premature stop codons are typically deleterious in nature; however, this stop codon, which occurs at the 3' terminus of APC, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 199 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. However, structural analysis suggests this deletion removes a known motif (Thr2841-Ser2842-Val2843) needed for protein binding involved in regulation of protein function (Zhang Z et al. PLoS ONE, 2011 Aug;6:e23507; Slep KC. PLoS ONE, 2012 Nov;7:e50097). This alteration has been described in numerous individuals with classic and attenuated Familial Adenomatous Polyposis and appears to be associated with the development of extra-colonic manifestations, particularly desmoid tumors (Burger B et al. Oncologist, 2011 Dec;16:1698-705; Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A., 1992 May;89:4452-6; Ikenoue T et al. Hum Genome Var, 2015 Mar;2:15011; Brensinger JD et al. Gut, 1998 Oct;43:548-52; Groden J et al. Am. J. Hum. Genet., 1993 Feb;52:263-72). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at