rs879253985

chr5-112844032-CAAAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000038.6(APC):c.8441_8444del(p.Lys2814SerfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,450,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T2813T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 8.34

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 Likely_pathogenic. Variant got 6 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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.8441_8444del	p.Lys2814SerfsTer26	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.8441_8444del	p.Lys2814SerfsTer26	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000841 AC: 2 AN: 237876 Hom.: 0 AF XY: 0.0000156 AC XY: 2 AN XY: 128428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000915

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1450384 Hom.: 0 AF XY: 0.00000693 AC XY: 5 AN XY: 721204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 16, 2023	This sequence change creates a premature translational stop signal (p.Lys2814Serfs*26) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the APC protein. This variant is present in population databases (rs765424268, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with biliary cancer (PMID: 26556299). ClinVar contains an entry for this variant (Variation ID: 245889). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2019	Not observed in large population cohorts (Lek 2016); Frameshift variant predicted to result in protein truncation as the last 30 amino acids are lost and replaced with 25 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; Disrupts a critical functional domain: hDLG binding domain (Azzopardi 2008); This variant is associated with the following publications: (PMID: 26556299) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2016	Variant summary: The c.8441_8444delAGAA (p.Lys2814Serfs) variant results in a premature termination codon, predicted to cause a truncated protein, which is a commonly known mechanism for disease. However, the variant affects an amino acid that is located 29 amino acids from the end of the protein coding region of the gene, and creates a premature termination 26 amino acids downstream, therefore the effect of this variant may be reduced considering its location. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0008% which does not exceed the maximal expected allele frequency for a pathogenic variant in APC (0.006%). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 26, 2020	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with biliary cancer (PMID: 26556299). This variant has also been identified in 2/237876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this C-terminal truncation variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 22, 2024	The c.8441_8444delAGAA variant, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 8441 to 8444, causing a translational frameshift with a predicted alternate stop codon (p.K2814Sfs*26). This alteration, designated c.8439_8442delAAAG, has been previously identified in the germline and tumor of an individual with biliary carcinoma, but polyp history was not provided (Schrader KA et al. JAMA Oncol. 2016 Jan;2(1):104-11). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of APC and impacts only the last 30 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 05, 2023

This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with biliary cancer (PMID: 26556299). This variant has also been identified in 2/237876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this C-terminal truncation variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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: rs879253985; hg19: chr5-112179729;