5-112707883-G-T

Variant names:

• chr5-112707883-G-T
• rs1239946140
• NM_001407446.1:c.165+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001407446.1(APC):​c.165+1G>T variant causes a splice donor, 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 pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APC NM_001407446.1 splice_donor, intron
• Scores: Splicing: ADA: 0.9885
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.165+1G>T		splice_donor_variant, intron_variant	Intron 1 of 15		NP_001394375.1
APC	NM_001407447.1	c.-19+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16		NP_001394376.1
APC	NM_001407448.1	c.-19+234G>T		intron_variant	Intron 1 of 16		NP_001394377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000509732.6	c.-19+234G>T		intron_variant	Intron 1 of 15	4		ENSP00000426541.2
APC	ENST00000507379.6	c.165+1G>T		splice_donor_variant, intron_variant	Intron 1 of 13	2		ENSP00000423224.2
APC	ENST00000505350.2	n.165+1G>T		splice_donor_variant, intron_variant	Intron 1 of 15	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-19+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16			ENSP00000518937.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1216204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 594044

African (AFR) AF: 0.00 AC: 0 AN: 28210

American (AMR) AF: 0.00 AC: 0 AN: 30674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20934

East Asian (EAS) AF: 0.00 AC: 0 AN: 24196

South Asian (SAS) AF: 0.00 AC: 0 AN: 76792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 969730

Other (OTH) AF: 0.00 AC: 0 AN: 48144

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Benign	0.62	D
PhyloP100		3.3
GERP RS		4.0
PromoterAI		0.011	Neutral
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88

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

Other links and lift over

dbSNP: rs1239946140; hg19: chr5-112043580;