rs1060503327

chr5-112838831-TGA-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000038.6(APC):c.3241_3242del(p.Ser1081HisfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1080E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.96

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 16 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 687 pathogenic variants in the truncated region.
• PP5: Variant 5-112838831-TGA-T is Pathogenic according to our data. Variant chr5-112838831-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 411476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838831-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.3241_3242del	p.Ser1081HisfsTer2	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.3241_3242del	p.Ser1081HisfsTer2	frameshift_variant	16/16	5	NM_000038.6	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2017

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 an individual with familial adenomatous polyposis (FAP) (PMID: 9375853). In addition, multiple truncating variants downstream of this truncation have been reported as pathogenic in individuals with FAP (PMID: 17064931). This variant is also known as 3239delAG (T1082X) in the literature. This sequence change deletes 2 nucleotides from exon 16 of the APC mRNA (c.3241_3242delAG), causing a frameshift at codon 1081. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Ser1081Hisfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2020

The c.3241_3242delAG pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 3241 to 3242, causing a translational frameshift with a predicted alternate stop codon (p.S1081Hfs*2). This mutation (referred to as 3239delAG) has been reported in an individual from northwest England who was diagnosed with familial adenomatous polyposis (Armstrong JG et al. Hum. Mutat. 1997; 10(5):376-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, 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: rs1060503327; hg19: chr5-112174528;