5-112775742-G-C

Position:

• chr5-112775742-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000038.6(APC):​c.531+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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_region, intron
• Scores: Splicing: ADA: 0.9971
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.98

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]

APC (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 3: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF was below the threshold]
• PP5: Variant 5-112775742-G-C is Pathogenic according to our data. Variant chr5-112775742-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 279681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112775742-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.531+5G>C		splice_region_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.531+5G>C		splice_region_variant, intron_variant		5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 19

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:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 27, 2023	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12010888]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 01, 2021	This variant has been observed in several individuals and families affected with familial adenomatous polyposis (PMID: 12010888, 19196998). Intron 5 is also known as intron 4 in the literature due to alternative exon numbering. ClinVar contains an entry for this variant (Variation ID: 279681). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 5 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein, but it affects a nucleotide within the consensus splice site of the intron. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing showed that this variant results in the out-of-frame skipping of exon 5 (PMID: 19196998, 12010888). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2016

This variant is denoted APC c.531+5 G>C or IVS5+5 G>C and consists of a G>C nucleotide substitution at the +5 position of intron 5 of the APC gene. This variant has been observed in at least two individuals presenting with a phenotype suggestive of Attenuated Familial Adenomatous Polyposis (Moisio 2002, Kaufmann 2009). Importantly, Kaufmann et al. (2009) found via mRNA analysis that APC c.531+5 G>C results in the heterozygous deletion of exon 5 (published as exon 4 due to the use of alternate nomenclature). APC c.531+5 G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations and the guanine (G) nucleotide that is altered is well conserved across species. Based on the current evidence, we consider APC c.531+5 G>C to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2020

The c.531+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 4 in the APC gene. This alteration has been previously observed in families with both classic familial adenomatous polyposis (FAP) and attenuated FAP (Moisio AL et al. Gut 2002 Jun;50(6):845-50; Friedl W et al. Hered. Cancer Clin. Pract. 2005 Sep;3(3):95-114; Kaufmann A et al. J. Mol. Diagn. 2009 Mar;11(2):131-9). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. In addition, RT-PCR analyses have confirmed that this alteration leads to exon 4 skipping, causing a frameshift and resultant truncated protein (Kaufmann A et al. J. Mol. Diagn. 2009 Mar;11(2):131-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779798; hg19: chr5-112111439;