rs387906231
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.509_512delATAG(p.Asp170ValfsTer4) 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. D170D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000038.6 frameshift
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.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.509_512delATAG | p.Asp170ValfsTer4 | frameshift_variant | Exon 5 of 16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.509_512delATAG | p.Asp170ValfsTer4 | frameshift_variant | Exon 5 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:7
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The APC p.Asp170ValfsX4 variant was identified in 13 of 4400 proband chromosomes (frequency: 0.003) from Dutch, German, French and French (Quebec) Canadian individuals or families with FAP (van der Luijt 1997, Friedl 2005, Jarry 2011, Lagarde 2010). The variant was also identified in a genome wide study of cancer genes in non-BRCA mutation individuals, in 1 individual with polyposis with no family history (Foley 2015). The variant was also identified in dbSNP (ID: rs387906231) “With Pathogenic allele”, ClinVar (classified pathogenic by Ambry Genetics, OMIM, and Mayo Clinic Genetic Testing Laboratories), Clinvitae (3x), UMD-LSDB (39x as causal), and Insight Colon Cancer Gene Variant Database (22x). The variant was not identified in Genesight-COGR, Cosmic, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Asp170ValfsX4 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 170 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
This sequence change creates a premature translational stop signal (p.Asp170Valfs*4) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 1324223, 10768871, 11247896, 19793053, 20223039, 20685668, 21779980, 22987206). ClinVar contains an entry for this variant (Variation ID: 804). For these reasons, this variant has been classified as Pathogenic. -
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The c.509_512del (p.Asp170Valfs*4) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 5 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in > 8 probands meeting phenotypic criteria, resulting in a total phenotype score of 5 (PS4, PMID 1324223, Ambry Genetics, Invitae, Leiden, Bonn, Melbourne internal data). In addition, this variant has been reported to segregate with FAP in > 10 affected meioses in 1 family (PP1_Moderate; PMID 1324223). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4, PM2_Supporting, PP1_Moderate (VCEP specifications version 1; date of approval: 12/12/2022). -
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not provided Pathogenic:4
This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals and families affected with familial adenomatous polyposis in the published literature (PMID: 22987206 (2013), 21779980 (2011), 20685668 (2010), 20223039 (2005)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -
Frameshift 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31332616, 15108286, 19793053, 21779980, 22987206, 20223039, 1324223) -
The APC c.509_512delATAG; p.Asp170fs variant (rs387906231), also known as c.505_508delATAG, is reported in the literature in multiple individuals affected with familial adenomatous polyposis (Dobbie 1996, Enomoto 2000, Filipe 2009, Friedl 2001, Friedl 2005, Miyaki 1994, van der Luijt 1997). This variant is reported in ClinVar (Variation ID: 804), and is absent from the Genome Aggregation Database, but is considered a low confidence variant in the database. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function variants in APC are a common mechanism for pathogenicity, and several downstream truncating nonsense and frameshift variants have been reported in individuals with familial adenomatous polyposis (Friedl 2005, Kerr 2013). Based on available information, this variant is considered to be pathogenic. References: Dobbie Z et al. Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene. J Med Genet. 1996 Apr;33(4):274-80. Enomoto M et al. The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis. Jpn J Clin Oncol. 2000 Feb;30(2):82-8. Filipe B et al. APC or MUTYH mutations account for the majority of clinically well-characterized families with FAP and AFAP phenotype and patients with more than 30 adenomas. Clin Genet. 2009 Sep;76(3):242-55. Friedl W et al. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut. 2001 Apr;48(4):515-21. 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. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. 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. van der Luijt RB et al. Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat. 1997;9(1):7-16. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 4 nucleotides in exon 5 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 reported in individuals affected with familial adenomatous polyposis (PMID: 1324223, 8730280, 10768871, 19793053, 20223039, 20685668, 21779980, 22987206). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The c.509_512delATAG pathogenic mutation, located in coding exon 4 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 509 to 512, causing a translational frameshift with a predicted alternate stop codon (p.D170Vfs*4). This alteration has been reported in multiple individuals and families with familial adenomatous polyposis (FAP) or attenuated FAP (AFAP) across various ethnicities (Fodde R et al. Genomics. 1992 Aug;13(4):1162-8; Enomoto M et al. Jpn. J. Clin. Oncol. 2000 Feb;30:82-8; Bisgaard ML et al. Hum Mutat 2004 May;23(5):522; Friedl W and Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Filipe B et al. Clin. Genet. 2009 Sep;76:242-55; Lagarde A et al. J Med Genet 2010 Oct;47 (10):721-2; Jarry J et al. Fam. Cancer, 2011 Dec;10:659-65; Schwarzová L et al. Fam Cancer 2013 Mar;12(1):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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Familial multiple polyposis syndrome Pathogenic:1
Variant summary: APC c.509_512delATAG (p.Asp170ValfsX4) 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. The variant was absent in 242340 control chromosomes and c.509_512delATAG has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (example, Fodde_1992, Cao_2006, Sieber_2006, Friedl_2001). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all submittions classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at