chr5-112754960-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_001354906.2(APC):c.-966C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000178 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
APC
NM_001354906.2 5_prime_UTR_premature_start_codon_gain
NM_001354906.2 5_prime_UTR_premature_start_codon_gain
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.58
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 Uncertain_significance. Variant got 5 ACMG points.
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.625
PP5
Variant 5-112754960-C-T is Pathogenic according to our data. Variant chr5-112754960-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184702.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=11, Likely_pathogenic=3}. Variant chr5-112754960-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251240Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135774
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461502Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727066
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:16Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:5Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 10, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 04, 2024 | Truncating variant in the 5' end of APC which has historically been considered to be associated with AFAP and lower penetrance. However, APC c.70C>T p.(Arg24*) is present in gnomAD at a frequency >0.001% and has also been observed in many healthy adults. According to the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0 this variant could possibly even reach a benign status (PVS1_not applicable, BS1, BS2). In the absence of formal case-control data, a classification as a variant of uncertain significance was applied. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Arg24*) 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). This variant is present in population databases (rs145945630, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and attenuated familial adenomatous polyposis (FAP) (PMID: 12034871, 16461775, 18433509, 25980754). ClinVar contains an entry for this variant (Variation ID: 184702). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 16, 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 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 22, 2021 | The APC c.70C>T (p.Arg24Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). Pathogenic variants in the 5’ end of the APC gene have been shown to be associated with an attenuated form of familial adenomatous polyposis since alternative translational initiation at codon 184 may result in a partially functional APC protein (PMID: 12034871, 16461775, 18433509). This variant has a maximum non-founder subpopulation frequency of 0.0016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112090657-C-T). It has been reported in individuals with a personal and/or family history of attenuated familial adenomatous polyposis (PS4; PMID: 18433509, internal data), colorectal cancer (PMID: 28135145), and suspected Lynch syndrome (PMID: 25980754). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 23, 2023 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 06, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2022 | Nonsense 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); This variant is associated with the following publications: (PMID: 28590426, 26681312, 25980754, 30322717, 30720243, 31447099, 29625052, 26689913, 33442023, 32980694, 18433509) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2021 | The p.R24* pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the APC gene, results from a C to T substitution at nucleotide position 70. This changes the amino acid from an arginine to a stop codon within coding exon 1. This mutation has been reported in a Swedish individual diagnosed with attenuated FAP, a phenotype that supports the proposed thought of a milder form of polyposis caused by mutations in the 5' end of the gene (Kanter-Smoler G et al. BMC Med. 2008 Apr;6:10). 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. However, alterations that result in premature termination in coding exon 1 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2023 | This variant changes 1 nucleotide in exon 2 of the APC gene, creating a premature translation stop signal. Alterations that cause premature truncation in the amino (N-) terminus of the APC protein have been associated with an attenuated phenotype and may have reduced penetrance and/or expressivity in comparison to classic familial adenomatous polyposis syndrome (FAP; PMID: 9585611, 11257105). This nonsense variant has been observed in individuals affected with attenuated familial adenomatous polyposis (AFAP) as well as in individuals lacking clinical features of AFAP (PMID: 18433509, communications with external laboratories), which suggests that this variant may have reduced penetrance and/or expressivity compared to individuals with conventional AFAP (PMID: 34666312). This variant also has been reported in an individual affected with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 7/282632 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 Likely Pathogenic with reduced penetrance. - |
Familial multiple polyposis syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 03, 2020 | The p.Arg24X variant in APC has been reported in 1 individual with attenuated familial adenomatous polyposis (AFAP) and 1 individual with suspected Lynch syndrome (Kanter-Smoler 2008, Yurgelun 2015) and has also been reported by other clinical laboratories in ClinVar (Variant ID 184702). It has been identified in 4/25788 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 24, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the APC gene is an established disease mechanism in individuals with FAP. However, truncating variants in the 5' end of the APC gene, where this variant is located, have typically been associated with AFAP (Jasperson 2017). In summary, this variant meets criteria to be classified as pathogenic for FAP, likely in the attenuated form, in an autosomal dominant manner, based upon predicted impact to the protein, presence in affected individuals, and frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS4_supporting. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 12, 2017 | - - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC p.Arg24X variant was identified in 2 of 2712 proband chromosomes (frequency: 0.0007) from individuals or families with attenuated familial adenomatous polyposis (AFAP) (Kanter-Smoler 2008, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs145945630) as "With Pathogenic allele", ClinVar (5x, pathogenic/likely pathogenic), Clinvitae (2x, pathogenic), and the Insight Colon Cancer Gene Variant Database (1x). The variant was not identified in Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. This variant was identified in the Genome Aggregation Consortium (Feb 27, 2017) in 5 (0 homozygous) of 276948 chromosomes (freq. 0.00002) in the following populations: Finnish in 4 of 25788 chromosomes (freq. 0.0002) and European in 1 of 126482 chromosomes (freq. 0.000008). The p.Arg24X variant leads to a premature stop codon at position 24. This alteration would typically be predicted to result in a truncated or absent protein and loss of function. However, one study has demonstrated that for APC mutations closer to the 5’ terminus, an internal ribosome entry site is utilized to initiate translation at codon 184, resulting in a partially functional N-terminally truncated protein, which results in an attenuated phenotype (Heppner Goss 2002). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Attenuated familial adenomatous polyposis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2024 | Variant summary: APC c.70C>T (p.Arg24X) 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. Some truncating mutations in the 5' end of the APC gene have been found to be associated with an attenuated phenotype of familial adenomatous polyposis coli (AFAP), as it was demonstrated that a downstream in-frame alternative start codon (codon 184) may generate a partially functional protein (see e.g. PMID: 12034871). However, to our knowledge, no experimental evidence demonstrating this scenario has been reported for the variant of interest. The variant allele was found at a frequency of 2.4e-05 in 251240 control chromosomes. c.70C>T has been reported in the literature in an individual affected with AFAP (Kanter-Smoler 2008) and in an other individual affected with Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18433509, 25980754). ClinVar contains an entry for this variant (Variation ID: 184702). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Classic or attenuated familial adenomatous polyposis Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2024 | This variant changes 1 nucleotide in exon 2 of the APC gene, creating a premature translation stop signal. Alterations that cause premature truncation in the amino (N-) terminus of the APC protein have been associated with an attenuated phenotype and may have reduced penetrance and/or expressivity in comparison to classic familial adenomatous polyposis syndrome (FAP; PMID: 9585611, 11257105). This nonsense variant has been observed in individuals affected with attenuated familial adenomatous polyposis (AFAP) as well as in individuals lacking clinical features of AFAP (PMID: 18433509, communications with external laboratories), which suggests that this variant may have reduced penetrance and/or expressivity compared to individuals with conventional AFAP (PMID: 34666312). This variant also has been reported in an individual affected with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 7/282632 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 Likely Pathogenic with reduced penetrance. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
0.91, 0.90
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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