rs863224456
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.3183_3187del(p.Gln1062Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
APC
NM_000038.6 frameshift
NM_000038.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.72
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 189 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-112838773-TAAAAC-T is Pathogenic according to our data. Variant chr5-112838773-TAAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 88913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838773-TAAAAC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.3183_3187del | p.Gln1062Ter | frameshift_variant | 16/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.3183_3187del | p.Gln1062Ter | frameshift_variant | 16/16 | 5 | NM_000038.6 | ENSP00000257430 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250490Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135384
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461812Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727202
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:29
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 29, 2020 | PVS1, PS4_Mod, PP4 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | APC: PVS1:Strong, PM1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 24, 2023 | The APC c.3183_3187del (p.Gln1062*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in affected individuals with familial adenomatous polyposis (FAP) (PMIDs: 1316610 (1992), 8381579 (1993), 23159591 (2013), 26446593 (2016), 26625971 (2016), and 35189564 (2022)), medulloblastoma (PMIDs: 29351919 (2018), 29753700 (2018), and 31504825 (2020)), papillary thyroid carcinoma (PMID: 31469036 (2019), and breast and/or ovarian cancer (PMID: 31159747 (2019)). This variant was also reported to segregate with disease and occurred as de novo in unrelated patients (PMID: 8381579 (1993)). The frequency of this variant in the general population, 0.0000089 (1/112982 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 06, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2013 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variation is a deletion of five nucleotides at position 1062 of the APC protein, resulting in the formation of new stop codon. Thus, a premature protein. This results in premature termination of protein synthesis and inactivation of one allele. This particular mutation has been described in international literature in patients with Familial adenomatous polyposis (PMID: 1316610, PMID: 8162022, PMID: 15771908). This mutation has been described in the mutation database ClinVar (Variation ID: 55683). - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2022 | Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15024739, 1316610, 11106555, 20649969, 15951557, 8162051, 19029688, 20007843, 25248397, 28127413, 27143045, 30897307, 19531215, 31469036, 16088911, 11748858, 11933206, 9375853, 8381581, 10083733, 10363573, 12007223, 10646887, 9950360, 7833931, 8395941, 8730280, 8381579, 8544194, 8162022, 20223039, 8990002, 18433509, 14961559, 20333795, 26625971, 25832318, 28533537, 28331559, 28135145, 26840078, 28975465, 29351919, 22692730, 29753700, 31069152, 30720243, 31159747, 27000756, 26446593, 20924072, 16134147, 31504825, 31598872, 18629513) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Familial adenomatous polyposis 1 Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 22, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 03, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | This sequence change results in a premature translational stop signal in the APC gene (p.Gln1062*). This variant has been observed in several individuals affected with familial adenomatous polyposis (PMID: 1316610, 8162022, 15771908). ClinVar contains an entry for this variant (Variation ID: 88913) with 21 submissions all of which describe this variant 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). Therefore, this variant has been classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Molecular Genetics Centre of Cancer Research, N.N. Alexandrov National Cancer Centre of Belarus | May 28, 2018 | This sequence change (c.3183_3187delACAAA) creates a stop codon (p.Gln1062*) in exon 16 of the APC mRNA. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Gln1062*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1782 amino acid(s) of the APC protein. This variant is present in population databases (rs587779352, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 1316610, 8162022, 15771908). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88913). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. 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. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 03, 2023 | - - |
Familial multiple polyposis syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2019 | Variant summary: APC c.3183_3187delACAAA (p.Gln1062X) 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. The variant allele was found at a frequency of 4e-06 in 250490 control chromosomes (gnomAD). c.3183_3187delACAAA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Inra_2015, Miyoshi_1992, Papp_2016). These data indicate that the variant is very likely to be associated with disease. 11 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 5 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/250490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2022 | The c.3183_3187delACAAA pathogenic mutation (also known as p.Q1062*), located in coding exon 15 of the APC gene, results from a deletion of 5 nucleotides at nucleotide positions 3183 to 3187. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This mutation has been identified in numerous individuals and families from a variety of ethnic backgrounds with classic familial adenomatous polyposis (FAP), including some individuals with extra colonic manifestations including desmoid tumors, gastrointestinal cancers, papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and epidermal cysts (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May;89:4452-6; Won YJ et al. J. Hum. Genet. 1999;44:103-8; González S et al. Cancer Genet. Cytogenet. 2005 Apr;158:70-4; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Friedl W & Aretz S. Hered. Cancer Clin. Pract. 2005 Sep;3:95-114; Plawski A & Slomski R. J. Appl. Genet. 2008;49:407-14; Fostira F et al. BMC Cancer. 2010 Jul;10:389; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J. Mol. Diagn. 2013 Jan;15:31-43; Papp J et al. Fam. Cancer. 2016 Jan;15(1):85-97; Dahl NA et al. J. Pediatr. Hematol. Oncol. 2016 07;38(5):e154-7). Of note, this alteration is also described as a truncation at codon 1061 or codon 1060, and as c.3221_3225delACAAA in the literature. In addition to the clinical data presented in the literature, 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. - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Gln1062X variant has been described as a common hotspot mutation in the literature, with a founder effect in at least one population (from the Spanish Balearic Islands) (Fostira 2010, Gonzales 2005). In six studies it was identified in 36 of 4386 chromosomes (frequency: 0.008) from individuals or families with familial adenomatous polyposis or colorectal cancer (Aceto 2005, Fostira 2010, Gonzales 2005, Kerr 2012, Plawski 2008, Wallis 1999), and was absent in control chromosomes from these studies. The variant was also identified in several database searches, including: GeneInsight COGR (classified as pathogenic by a clinical laboratory), HGMD, UMD (208X as a “causal” variant), COSMIC, Clinvitae, InSiGHT Colon Cancer Database (191X), Zhejiang Colon Cancer Database, and the ClinVar Database (classified as pathogenic by Emory Genetics Laboratory, Pathway Genomics, and Ambry Genetics). The p.Gln1062X variant leads to a premature stop codon at position 1062, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. Notably, this variant occurs in the last exon of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Classic or attenuated familial adenomatous polyposis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 15, 2023 | This variant creates a premature termination codon in the last exon. The transcribed mRNA is predicted to escape nonsense mediated decay and result in protein truncation. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 9101302, 9375853, 9703421, 11677205, 23159591). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). - |
Craniopharyngioma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Feb 29, 2016 | This is a frameshift mutation in which 5 nucleotides are deleted between coding positions 3183 and 3187 and is predicted to shift the reading frame at codon 1061. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at