rs1554060285

Variant names:

• chr5-112707791-G-A
• rs1554060285
• NM_001407446.1:c.74G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112707791-G-A
• chr5-112707791-G-C
• chr5-112707791-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001407446.1(APC):​c.74G>A​(p.Trp25*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000575 in 1,218,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: APC NM_001407446.1 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.748
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 2310 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_001407446.1	c.74G>A	p.Trp25*	stop_gained	Exon 1 of 16		NP_001394375.1
APC	NM_001354897.2	c.74G>A	p.Trp25*	stop_gained	Exon 1 of 15		NP_001341826.1
APC	NM_001127511.3	c.74G>A	p.Trp25*	stop_gained	Exon 1 of 14		NP_001120983.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000507379.6	c.74G>A	p.Trp25*	stop_gained	Exon 1 of 14	2		ENSP00000423224.2
APC	ENST00000505350.2	n.74G>A		non_coding_transcript_exon_variant	Exon 1 of 16	3		ENSP00000481752.1
APC	ENST00000713636.1	n.-110G>A		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000518937.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000575 AC: 7 AN: 1218370 Hom.: 0 Cov.: 31 AF XY: 0.00000336 AC XY: 2 AN XY: 595226

African (AFR) AF: 0.00 AC: 0 AN: 28308

American (AMR) AF: 0.00 AC: 0 AN: 30760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21054

East Asian (EAS) AF: 0.00 AC: 0 AN: 24244

South Asian (SAS) AF: 0.00 AC: 0 AN: 76904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4894

European-Non Finnish (NFE) AF: 0.00000721 AC: 7 AN: 970788

Other (OTH) AF: 0.00 AC: 0 AN: 48294

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Sep 01, 2024

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. ClinVar contains an entry for this variant (Variation ID: 469794). 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	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.35	N
PhyloP100		0.75
GERP RS		2.1
PromoterAI		0.073	Neutral
Mutation Taster		=289/11	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1554060285; hg19: chr5-112043488;