rs1554079128

Positions:

• chr5-112815488-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.835-7T>G variant causes a splice region, 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.495

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112815488-T-G is Pathogenic according to our data. Variant chr5-112815488-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112815488-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.835-7T>G		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.835-7T>G		splice_region_variant, intron_variant		5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2023	ClinVar contains an entry for this variant (Variation ID: 433614). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 18433509). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individuals with familial adenomatous polyposis (PMID: 18433509; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 27, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18433509, 20649969, Myriad internal data]. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC c.835-7T>G variant was identified in 1 of 192 proband chromosomes (frequency 0.005) from individuals with familial adenomatous polyposis (FAP) (Kanter-Smoler 2008) and was also identified in the HGMD and the “InSIGHT Colon Cancer Databases”. The variant was not identified in dbSNP, Clinvitae database COSMIC, Zhejiang Colon Cancer Database (LOVD), ClinVar database, Clinvitae, GeneInsight-COGR databases, UMD, The NHLBI GO Exome Sequencing Project, the genome aggregation consortium (Feb 27, 2017), and the Exome Aggregation Consortium database (August 8, 2016). The variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing, with 4 of 5 different programs predicting the abolishment of the known splicing acceptor site at nucleotide position c.835, and 2 of 5 predicting the creation of a splicing acceptor site at the position of the variant, c.835-7. Additionally, Kanter-Smoler (2008) detected an aberrant APC polypeptide pattern produced by this variant in an RNA-based protein truncation test. The authors of this study suggest that this base substitution introduces a new splice acceptor site which is apparently preferred by the splicing machinery and results in the inclusion of the last six bases of intron 10 (alias exon 7) causing a frameshift, which alters the protein's amino acid sequence and results in a premature termination codon downstream. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 1
DS_AL_spliceai		0.73		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554079128; hg19: chr5-112151185; COSMIC: COSV104439186;