5-112828856-G-T

Position:

• chr5-112828856-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PS3_Moderate PM2_Supporting BP1

This summary comes from the ClinGen Evidence Repository: The c.1627G>T variant in APC is a missense variant predicted to cause a substitution of valine by phenylalanine at amino acid position 543 (p.Val543Phe). This variant is located at the first base of exon 14. RT-PCR of the exons flanking the target site in a patient with AFAP shows that the variant c.1627G>T impacts splicing by leading to exon 14 skipping, which is an in-frame event (PS3_Moderate; PMID22987206). This variant scored 0.5 phenotype points based on information available in 3 individuals (PS4_variable not met; PMID 22987206, Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In silico predictions by SpliceAI, MaxEntScan and VarSEAK showed conflicting results (PP3 not met). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_moderate, and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16024864/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 9.60

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 Uncertain_significance. Variant got 2 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP1: 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.1627G>T	p.Val543Phe	missense_variant, splice_region_variant	14/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1627G>T	p.Val543Phe	missense_variant, splice_region_variant	14/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.112G>T		splice_region_variant, non_coding_transcript_exon_variant	3/8	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 19, 2023	The c.1627G>T variant in APC is a missense variant predicted to cause a substitution of valine by phenylalanine at amino acid position 543 (p.Val543Phe). This variant is located at the first base of exon 14. RT-PCR of the exons flanking the target site in a patient with AFAP shows that the variant c.1627G>T impacts splicing by leading to exon 14 skipping, which is an in-frame event (PS3_Moderate; PMID22987206). This variant scored 0.5 phenotype points based on information available in 3 individuals (PS4_variable not met; PMID 22987206, Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In silico predictions by SpliceAI, MaxEntScan and VarSEAK showed conflicting results (PP3 not met). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_moderate, and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2023	Studies have shown that this missense change results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 22987206). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 490221). This missense change has been observed in individual(s) with clinical features of attenuated familial adenomatous polyposis (PMID: 22987206). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 543 of the APC protein (p.Val543Phe). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 14, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2024	The p.V543F variant (also known as c.1627G>T) is located in coding exon 13 of the APC gene. The valine at codon 543 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 13. This variant was detected in a 63-year-old patient that with reported attenuated FAP that underwent subtotal colectomy due to a "field of polyps" (Schwarzová L et al. Fam Cancer, 2013 Mar;12:35-42). Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;D;D;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Benign	1.8	.;L;L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.82, 0.80
MutPred		0.61		.;Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);.;
MVP		0.92
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.010		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: rs1554082080; hg19: chr5-112164553;