5-112780904-G-C

Position:

• chr5-112780904-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.645+1G>C variant causes a splice donor, intron 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APC NM_000038.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.99

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013244257 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of -32, new splice context is: tagGTacct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112780904-G-C is Pathogenic according to our data. Variant chr5-112780904-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1753603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112780904-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.645+1G>C		splice_donor_variant, intron_variant		ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.645+1G>C		splice_donor_variant, intron_variant		5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Apr 27, 2023

This variant is considered likely 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The c.645+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the APC gene. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Familial Adenomatous Polyposis (FAP) (Ambry internal data). Two other alterations at the same nucleotide position, c.645+1G>A and c.645+1G>T, have also been reported in patients with FAP (Stekrova J, BMC Med. Genet. 2007 ; 8():16; Olschwang S, Am. J. Hum. Genet. 1993 Feb; 52(2):273-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that c.645+1G>C will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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. Based on the supporting evidence, this variant is interpreted 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	0.36
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: -33
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-112116601;