rs1114167569

chr5-112835166-G-A

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000038.6(APC):c.1958+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.60

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-112835166-G-A is Pathogenic according to our data. Variant chr5-112835166-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 428125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835166-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1958+1G>A		splice_donor_variant		ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1958+1G>A		splice_donor_variant		5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

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 03, 2023	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 31, 2023	A known pathogenic variant is detected in the APC gene (c.1958+1G>A). This sequence change affects a donor splice site in intron 15 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 12007223, 15459959, 16088911, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 428125). Variants that disrupt the consensus splice site are a relatively of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 15 (also known as 14) and introduces a new termination codon (PMID: 15459959). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the APC gene are known to cause familial adenomatous polyposis, -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2020	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with skipping of exon 15 (PMID: 15459959). However, the mRNA is not expected to undergo nonsense-mediated decay. Exon 15 is also known as exon 14 in the literature. This variant has been observed in an several individuals affected with familial adenomatous polyposis (PMID: 15459959, 20685668, 12007223, 16088911,20223039). This variant has also been reported as IVS14+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 428125). This sequence change affects a donor splice site in intron 15 of the APC gene. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC c.1958+1G>A variant was identified in 4 of 4474 proband chromosomes (frequency: 0.001) from individuals or families with Familial Adenomatous Polyposis (Aretz 2004, Friedl 2005, Gavert 2002, Kim 2005). The variant was also identified in UMD (3x with a “causal” classification) and InSiGHT Colon Cancer Gene Variant Database (5x as Pathogenic). The variant was not identified in dbSNP, Clinvitae database, COSMIC, Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, NHLBI GO Exome Sequencing Project and Exome Aggregation Consortium database (August 8, 2016). The c.1958+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Furthermore, several studies confirm by RT-PCR that this variant lead to aberrant splicing causing a loss of exon 14 (protein change r. 1744_1958del, Aretz 2004, Gavert 2002, Kim 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2021

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Aretz 2004, Yedid 2016); Not observed in large population cohorts (Lek et al., 2016); Also known as IVS14+1G>A; This variant is associated with the following publications: (PMID: 28010732, 20223039, 12007223, 16088911, 11247896, 15459959, 20685668) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2019

The c.1958+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the APC gene. This alteration has been identified in multiple individuals with familial adenomatous polyposis (FAP) (Friedl W et al. Gut. 2001 Apr;48:515-21; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Gavert N et al. Hum. Mutat. 2002 Jun;19:664; Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2). Transcript analysis has also shown that this alteration leads to the skipping of coding exon 14 (Ambry internal data; Aretz S et al. Hum. Mutat. 2004 Nov;24:370-80). Of note, this mutation is also designated IVS14+1G>A in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1114167569; hg19: chr5-112170863; COSMIC: COSV57330281;