rs772745309

Positions:

• chr5-112834947-C-G
• chr5-112834947-C-T

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.1744-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7765
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: -0.0880

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant 5-112834947-C-G is Pathogenic according to our data. Variant chr5-112834947-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 433625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1744-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1744-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 433625). This variant has been observed in individual(s) with APC-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2022

The c.1744-4C>G intronic pathogenic mutation results from a C to G substitution 4 nucleotides upstream from coding exon 14 in the APC gene. This nucleotide position is poorly conserved in available vertebrate species. This alteration has been observed in at least one individual who has a personal and/or family history that is consistent with APC-associated disease (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC c.1744-4C>G variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in the COGR database. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.1744-4C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. In addition 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 1
DS_AL_spliceai		0.59		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs772745309; hg19: chr5-112170644;