rs878853458

Positions:

• chr5-112841510-CA-C

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.5917del​(p.Ser1973ValfsTer71) 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:4
• Conservation: PhyloP100: 8.95

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 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 5-112841510-CA-C is Pathogenic according to our data. Variant chr5-112841510-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 236624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112841510-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.5917del	p.Ser1973ValfsTer71	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.5917del	p.Ser1973ValfsTer71	frameshift_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

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	Jan 18, 2016	For these reasons, this variant has been classified as Pathogenic. Truncating variants in APC are known to be pathogenic. This particular truncation has been reported in the literature in an individual suspected of having familial adenomatous polyposis (PMID: 20223039). This sequence change deletes 1 nucleotide from exon 16 of the APC mRNA (c.5917delA), causing a frameshift at codon 1973. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Ser1973Valfs*71). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated APC protein by eliminating ~870 amino acid residues (~31%) from the full length protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2016	This sequence change deletes 1 nucleotide from exon 16 of the APC mRNA (c.5917delA), causing a frameshift at codon 1973. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Ser1973Valfs*71). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated APC protein by eliminating ~870 amino acid residues (~31%) from the full length protein. Truncating variants in APC are known to be pathogenic. This particular truncation has been reported in the literature in an individual suspected of having familial adenomatous polyposis (PMID: 20223039). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The c.5917delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 5917, causing a translational frameshift with a predicted alternate stop codon (p.S1973Vfs*71). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 871 amino acids of the protein. 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). This alteration was identified in 1/1164 unrelated German index patients with a clinical diagnosis of FAP or AFAP (Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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: rs878853458; hg19: chr5-112177207;