rs587781330

Positions:

• chr5-112841527-AAAAC-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.5936_5939delACAA​(p.Asn1979fs) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.90

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112841527-AAAAC-A is Pathogenic according to our data. Variant chr5-112841527-AAAAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 140863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112841527-AAAAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.5936_5939delACAA	p.Asn1979fs	frameshift_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.5936_5939delACAA	p.Asn1979fs	frameshift_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+12558_228+12561delACAA		intron_variant		3		ENSP00000454861.1

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 15, 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	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2023	This sequence change creates a premature translational stop signal (p.Asn1979Thrfs*64) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 865 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 clinical features of APC-related conditions (PMID: 9824584, 20434453, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140863). This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2022	Frameshift 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: 26681312, 24763289, 23159591, 31447099, 20434453, 17088437, 9824584, 1316610, 27081525, 22135120, 8381579) -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 06, 2018

The p.Asn1979fs variant in APC has been reported in at least 5 individuals with attenuated familial adenomatous polyposis (AFAP; Brensinger 1998, Castellsague 2 010), 5 that have been referred for APC clinical testing (Kerr 2013), and 1 ind ividual with a personal history of colonic polyps (Susswein 2015). The variant s egregated with AFAP in at least 5 affected relatives from 1 family (Brensinger 1 998). This variant has also been reported by other clinical laboratories in Clin Var (Variation ID: 140863) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1979 and leads to a premature termination codon 6 4 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncate d protein. An in vitro protein assay from patient RNA confirmed that this varian t leads to a truncated protein (Brensinger 1998). Truncating variants in the las t exon of APC have been reported in individuals with FAP. In summary, this vari ant meets criteria to be classified as pathogenic for APC-associated polyposis c onditions in an autosomal dominant manner based upon presence in multiple affect ed individuals, segregation studies, absence from the general population, and th e predicted impact on protein. ACMG/AMP Criteria applied (Richards 2015): PS4; P P1_Moderate; PM2; PM4. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2012

This alteration occurs at the 3' terminus of the APC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

APC-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The APC c.5936_5939delACAA variant is predicted to result in a frameshift and premature protein termination (p.Asn1979Thrfs*64). This variant has been reported in multiple individuals with APC-related diseases (Susswein et al 2015. PubMed ID: 26681312. Table S1; Brensinger et al. 1998. PubMed ID: 9824584; Castellsagué et al. 2010. PubMed ID: 20434453). This variant is not present in a large population database (https://gnomad.broadinstitute.org/) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140863/). Frameshift variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs587781330; hg19: chr5-112177224;