rs730881274
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.5936_5939del(p.Asn1979ThrfsTer64) 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. E1978E) 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: 8.90
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 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 139 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-112841527-AAAAC-A is Pathogenic according to our data. Variant chr5-112841527-AAAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 140863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112841527-AAAAC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.5936_5939del | p.Asn1979ThrfsTer64 | frameshift_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5936_5939del | p.Asn1979ThrfsTer64 | 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:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 15, 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 | Oct 27, 2023 | This sequence change creates a premature translational stop signal (p.Asn1979Thrfs*64) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 865 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 9824584, 20434453, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140863). This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2022 | Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 24763289, 23159591, 31447099, 20434453, 17088437, 9824584, 1316610, 27081525, 22135120, 8381579) - |
Familial multiple polyposis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 06, 2018 | The p.Asn1979fs variant in APC has been reported in at least 5 individuals with attenuated familial adenomatous polyposis (AFAP; Brensinger 1998, Castellsague 2 010), 5 that have been referred for APC clinical testing (Kerr 2013), and 1 ind ividual with a personal history of colonic polyps (Susswein 2015). The variant s egregated with AFAP in at least 5 affected relatives from 1 family (Brensinger 1 998). This variant has also been reported by other clinical laboratories in Clin Var (Variation ID: 140863) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1979 and leads to a premature termination codon 6 4 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncate d protein. An in vitro protein assay from patient RNA confirmed that this varian t leads to a truncated protein (Brensinger 1998). Truncating variants in the las t exon of APC have been reported in individuals with FAP. In summary, this vari ant meets criteria to be classified as pathogenic for APC-associated polyposis c onditions in an autosomal dominant manner based upon presence in multiple affect ed individuals, segregation studies, absence from the general population, and th e predicted impact on protein. ACMG/AMP Criteria applied (Richards 2015): PS4; P P1_Moderate; PM2; PM4. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2012 | This alteration occurs at the 3' terminus of the APC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on the supporting evidence, 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 | Feb 01, 2024 | The APC c.5936_5939delACAA variant is predicted to result in a frameshift and premature protein termination (p.Asn1979Thrfs*64). This variant has been reported in multiple individuals with APC-related diseases (Susswein et al 2015. PubMed ID: 26681312. Table S1; Brensinger et al. 1998. PubMed ID: 9824584; Castellsagué et al. 2010. PubMed ID: 20434453). This variant is not present in a large population database (https://gnomad.broadinstitute.org/) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140863/). 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