rs876660375

Positions:

• chr5-112844108-C-A
• chr5-112844108-C-G
• chr5-112844108-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.8514C>A variant in APC is a variant predicted to cause a premature stop codon at position 2838 (p.Tyr2838*) in exon 16, downstream of codon 2645. As a result, the PVS1 rule is not applicable. This variant has been reported in 2 probands meeting phenotype criteria, resulting in a total phenotype score of 2 (PS4_moderate, Ambry and Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this is a Variant of Unknown Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_moderate and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16039798/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 2.62

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 Uncertain_significance. Variant got 3 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.8514C>A	p.Tyr2838Ter	stop_gained	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.8514C>A	p.Tyr2838Ter	stop_gained	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2020	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 486740). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr2838*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the APC protein. -
Uncertain significance, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	The c.8514C>A variant in APC is a variant predicted to cause a premature stop codon at position 2838 (p.Tyr2838*) in exon 16, downstream of codon 2645. As a result, the PVS1 rule is not applicable. This variant has been reported in 2 probands meeting phenotype criteria, resulting in a total phenotype score of 2 (PS4_moderate, Ambry and Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this is a Variant of Unknown Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_moderate and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The p.Y2838* variant (also known as c.8514C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 8514. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This substitution and subsequent stop codon occur at the 3' terminus of APC and impact only the last 6 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, structural analysis suggests this deletion removes a known motif (Thr2841-Ser2842-Val2843) needed for protein binding involved in regulation of protein function (Slep KC et al, PLoS ONE 2012; 7(11):e50097 ; Zhang Z et al, PLoS ONE 2011 ; 6(8):e23507). 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_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.72
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660375; hg19: chr5-112179805;