chr5-112838220-C-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.2626C>T(p.Arg876*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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. R876R) has been classified as Likely benign.
Frequency
Consequence
NM_000038.6 stop_gained
Scores
Clinical Significance
Conservation
Publications
- classic or attenuated familial adenomatous polyposisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- desmoid tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- familial adenomatous polyposis 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- gastric adenocarcinoma and proximal polyposis of the stomachInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- APC-related attenuated familial adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Turcot syndrome with polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cenani-Lenz syndactyly syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | MANE Select | c.2626C>T | p.Arg876* | stop_gained | Exon 16 of 16 | NP_000029.2 | ||
| APC | NM_001407446.1 | c.2710C>T | p.Arg904* | stop_gained | Exon 16 of 16 | NP_001394375.1 | |||
| APC | NM_001354896.2 | c.2680C>T | p.Arg894* | stop_gained | Exon 17 of 17 | NP_001341825.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | TSL:5 MANE Select | c.2626C>T | p.Arg876* | stop_gained | Exon 16 of 16 | ENSP00000257430.4 | ||
| APC | ENST00000508376.6 | TSL:1 | c.2626C>T | p.Arg876* | stop_gained | Exon 17 of 17 | ENSP00000427089.2 | ||
| APC | ENST00000502371.3 | TSL:1 | n.*824C>T | non_coding_transcript_exon | Exon 12 of 12 | ENSP00000484935.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:7
ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate
This sequence change creates a premature translational stop signal (p.Arg876*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1968 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 (PMID: 8187091, 12581900, 14961559, 17411426, 19029688, 20223039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216014). 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.
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
The observed stop gained c.2626C>T (p.Arg876Ter) variant in APC gene has been previously reported in multiple individuals and families affected with familial adenomatous polyposis (Friedl and Aretz, 2005; Stekrova et al., 2007; Kanter-Smoler et al., 2008; Ciavarella et al., 2018; Li et al., 2019). It has also been observed to segregate with disease in related individuals. The p.Arg876Ter variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg876Ter in APC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg876Ter) in the APC gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in APC gene have been previously reported to be pathogenic (Kanter-Smoler et al., 2008). For these reasons, this variant has been classified as Pathogenic.
not provided Pathogenic:7
PP1, PP4, PM2, PS4_moderate, PVS1_strong
The APC c.2626C>T (p.Arg876*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in individuals with familial adenomatous polyposis (PMID: 39046601 (2024), 31062380 (2019), 29367705 (2018), 20223039 (2005), 19029688 (2008), 17411426 (2007), 14961559 (2003), 12581900 (2003), 8187091 (1994)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33294277, 29367705, 24651453, 25623536, 25025766, 25695693, 25832318, 34897210, 7833931, 18433509, 34655802, 19029688, 20223039, 8187091, 19347965, 12581900, 23159591, 25307848, 20007843, 17653897, 14729851, 27146902, 26446593, 26625971, 17411426, 14961559, 15108288, 10646887, 39096151)
PVS1, PS4, PM2_SUP
not specified Pathogenic:1
The APC c.2626C>T; p.Arg876Ter variant (rs121913333) is reported in the literature in multiple individuals and families affected with familial adenomatous polyposis (De Rosa 2003, Ficari 2000, Friedl 2005, Hashimoto 2015, Kanter-Smoler 2008, Lagarde 2010, Mihalatos 2003, Miyaki 1994, Stekrova 2007, Stella 1994). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 216014) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the APC gene. While this may not lead to nonsense-mediated decay, it is expected to truncate 1,968 amino acids and is predicted to result in a nonfunctional protein. Based on available information, this variant is considered to be pathogenic. References: De Rosa M et al. The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations. Hum Mutat. 2003 Jun;21(6):655-6. Ficari F et al. APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. Br J Cancer. 2000 Jan;82(2):348-53. Friedl W and Aretz S. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Hashimoto T et al. Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features. Histopathology. 2015 Nov;67(5):689-98. Kanter-Smoler G et al. Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families. BMC Med. 2008 Apr 24;6:10. Lagarde A et al. Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. J Med Genet. 2010 Oct;47(10):721-2. Mihalatos M et al. Novel mutations of the APC gene in familial adenomatous polyposis in Greek patients. Cancer Genet Cytogenet. 2003 Feb;141(1):65-70. Miyaki M et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20. Stekrova J et al. Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. BMC Med Genet. 2007 Apr 5;8:16. Stella A et al. Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients. Hum Mol Genet. 1994 Sep;3(9):1687-8.
Carcinoma of colon Pathogenic:1
The p.Arg876X variant has not been previously identified by our laboratory, but has been reported and in the literature in 36 out of 6228 proband chromosomes in individuals with FAP, HNPCC, and sporadic colorectal carcinoma. It was not found in any of the 400 control chromosomes (Friedl, Aretz 2005, Goranova 2011, Albuquerque 2010, Liu 2007, Miyaki 1994, Powell 1992, Plawksi 2008, Dymerska 2010, Ruruuchi 2000, Albuquerque 2002, Olschwang 1997, Stekrova 2007, Scheel 2010). The variant leads to a premature stop codon at position 876 which is predicted to cause premature truncation of the protein product and loss of function. Loss of function of the APC gene is an established mechanism of familial adenomatous polyposis. In summary based on the above information, this variant is classified as pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.R876* pathogenic mutation (also known as c.2626C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2626. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been previously reported in multiple individuals with familial adenomatous polyposis (FAP) syndrome (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43; Ficari F et al. Br. J. Cancer, 2000 Jan;82:348-53; De Rosa M et al. Hum. Mutat., 2003 Jun;21:655-6; Mihalatos M et al. Cancer Genet. Cytogenet., 2003 Feb;141:65-70; Kanter-Smoler G et al. BMC Med, 2008 Apr;6:10; Lagarde A et al. J. Med. Genet. 2010 Oct;47(10):721-2; Zhang S et al. Gene, 2016 Feb;577:187-92; Ciavarella M et al. Eur. J. Hum. Genet. 2018 03;26(3):387-395). 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.
Neoplasm Other:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at