rs387906231

Positions:

• chr5-112775710-AATAG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.509_512del​(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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 9.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112775710-AATAG-A is Pathogenic according to our data. Variant chr5-112775710-AATAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 804.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr5-112775710-AATAG-A is described in Lovd as [Pathogenic]. Variant chr5-112775710-AATAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.509_512del	p.Asp170ValfsTer4	frameshift_variant	5/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.509_512del	p.Asp170ValfsTer4	frameshift_variant	5/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 26, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 05, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -
Pathogenic, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 18, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	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. -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 30, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2023	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) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2022	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. -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 22, 2021

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906231; hg19: chr5-112111407;