5-112838934-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.3340C>T(p.Arg1114*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1114R) has been classified as Likely benign.
Frequency
Consequence
NM_000038.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:5
This sequence change creates a premature translational stop signal (p.Arg1114*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1730 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 familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1338764, 16134147, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 236589). 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, internal data). 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. -
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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The variant NM_000038.6:c.3340C>T (chr5:112838934) in APC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -
not provided Pathogenic:3
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Published functional studies demonstrate damaged APC protein function (PMID: 14633595); 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: 1316610, 23159591, 1338764, 24664542, 19793053, 28007021, 20223039, 16134147, 20685668, 20924072, 37937776, 14633595, 34897210, 22987206) -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.R1114* pathogenic mutation (also known as c.3340C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3340. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been reported in multiple families with familial adenomatous polyposis (FAP) (Nagase H et al. Hum. Mutat. 1992;1:467-73; Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Schwarzová L et al. Fam. Cancer, 2013 Mar;12:35-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with polyposis and familial adenomatous polyposis (PMID: 1338764, 20685668, 20223039, 16134147). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Familial multiple polyposis syndrome Pathogenic:1
Variant summary: APC c.3340C>T (p.Arg1114X) 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 (c.3927_3931delAAAGA, p.Glu1309fsX4; c.4393_4394dupAG, p.Ser1465fsX9; c.5582_5585delCTTT, p.Ser1861fsX1). The variant was absent in 245192 control chromosomes. c.3340C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Ficari_2000, Friedl_2005, Kanter-Smoler_2008). These data indicate that the variant is very likely to be associated with disease. 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Carcinoma of colon Pathogenic:1
The p.Arg1114X variant was identified in 17 of 3924 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis or colorectal cancer, and was not identified in 158 control chromosomes from healthy individuals (Aceto 2005; Ficari 2000; Friedl 2005; Kanter-Smoler 2008; Liu 2007; Nagase 1992; Rivers 2010; van der Luijt 1997; Vandrovcova 2004). The p.Arg1114X variant was also identified in dbSNP (ID: rs121913331), HGMD, UMD (25X), “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and the COSMIC database. This variant is in the last exon and truncating variants in this region of the RNA may sometimes be subject to nonsense mediated RNA decay; this cannot be predicted. However, the p.Arg1114X variant leads to a premature stop codon at position 1114, 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. In addition, Liu (2007) identified this variant in tumour tissues and predict it as a hot spot mutation with higher rate of cancer metastasis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at