rs1064793020
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.233_236del(p.Asp78AlafsTer7) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L77L) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 frameshift
NM_000038.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.90
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-112767197-TTAGA-T is Pathogenic according to our data. Variant chr5-112767197-TTAGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 418005.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.233_236del | p.Asp78AlafsTer7 | frameshift_variant | 4/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.233_236del | p.Asp78AlafsTer7 | frameshift_variant | 4/16 | 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:7
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 | Jan 03, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418005). This variant is also known as c.232_235del4. This premature translational stop signal has been observed in individual(s) with attenuated familial adenomatous polyposis (AFAP) (PMID: 8252630). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp78Alafs*7) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 25, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | APC: PP1:Strong, PVS1:Strong, PM2, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in the published literature (Spirio 1993); This variant is associated with the following publications: (PMID: 8252630) - |
Familial multiple polyposis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2021 | Variant summary: APC c.233_236delATAG (p.Asp78AlafsX7) 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. The variant was absent in 251310 control chromosomes (gnomAD). c.233_236delATAG has been reported in the literature in individuals affected with attenuated form of Familial Adenomatous Polyposis (example, Spirio_1993, Wu_2001, Wang_2019). This variant is also known as c.232_235del4 and c.230_233_delTAGA in the literature (Spirio_1993, Wu_2001 and Wang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2022 | The c.233_236delATAG pathogenic mutation, located in coding exon 3 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 233 to 236, causing a translational frameshift with a predicted alternate stop codon (p.D78Afs*7). This mutation was identified in a kindred affected with attenuated FAP (Spirio L et al. Cell, 1993 Dec;75:951-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
APC-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 09, 2023 | The APC c.233_236delATAG variant is predicted to result in a frameshift and premature protein termination (p.Asp78Alafs*7). This variant has been reported in a family to be causative for attenuated adenomatous polyposis coli (Spirio et al. 1993. PubMed ID: 8252630, kindred 6). This variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/418005/?new_evidence=true). Frameshift variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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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