rs1554085303
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.3783_3784delTT(p.Tyr1262fs) 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: 7.67
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 125 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112839376-CTT-C is Pathogenic according to our data. Variant chr5-112839376-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 537503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.3783_3784delTT | p.Tyr1262fs | frameshift_variant | 16/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
| ENSG00000258864 | ENST00000520401.1 | n.228+10405_228+10406delTT | intron_variant | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: 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 | Labcorp Genetics (formerly Invitae), Labcorp | May 09, 2021 | This sequence change results in a premature translational stop signal in the APC gene (p.Tyr1262Leufs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1,582 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. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. 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 reported in several individuals affected with familial adenomatous polyposis (PMID: 8111416, 15108288, 17963004). ClinVar contains an entry for this variant (Variation ID: 537503). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 09, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Familial multiple polyposis syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 17, 2019 | Variant summary: APC c.3783_3784delTT (p.Tyr1262LeufsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3927_3931delAAAGA (p.Glu1309fsX4), c.4393_4394dupAG (p.Ser1465fsX9)). The variant was absent in 250350 control chromosomes (gnomAD). c.3783_3784delTT has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Tamura_1993, Rosa_2004, Truta_2005, DeLaFuente_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) has cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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