5-112828972-G-C

Variant names:

• chr5-112828972-G-C
• rs1114167592
• NM_000038.6:c.1743G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000038.6: c.1743G>C (p.?) variant in APC is a G to non-G change at the last nucleotide of exon 14. It is predicted to cause skipping of exon 14, resulting in an in-frame deletion of an exon with sufficient supportive clinical data (PVS1_strong). This variant has been reported in 1 family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_supporting [Ambry Genetics]). The variant has been reported in 5 additional probands with a colorectal cancer / polyposis associated phenotype not meeting phenotypic criteria (Invitae, Ambry Genetics) and 1 proband without any clinical information (GeneDX). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1_strong, PS4_supporting and PM2_supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16025124/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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 rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1743G>C	p.Lys581Asn	missense_variant, splice_region_variant	Exon 14 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1743G>C	p.Lys581Asn	missense_variant, splice_region_variant	Exon 14 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 8	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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:1

Jun 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 581 of the APC protein (p.Lys581Asn). This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial adenomatous polyposis (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428153). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not provided Pathogenic:1

Mar 15, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20223039, 18199528, 19196998) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 19, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1743G>C variant (also known as p.K581N), located in coding exon 13 of the APC gene, results from a G to C substitution at nucleotide position 1743. The lysine at codon 581 is replaced by asparagine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. An adjacent alteration at the penultimate nucleotide position of coding exon 13 (c.1742A>G) is a well-described mutation seen in a family with attenuated FAP that has been shown by functional mRNA studies to lead to aberrant splicing and in-frame skipping of coding exon 13 (Kaufmann A et al. J Mol Diagn. 2009 Mar; 11(2):131-9). Using the BDGP splice site prediction tool, c.1743G>C is predicted to result in a weakening of the native splice donor site, and using the ESEfinder splice site prediction tool, c.1743G>C is predicted to result in abolishment of the native splice donor site; however, direct evidence is unavailable. Of note, ESEfinder and BDGP are predicting a stronger impact on splicing for c.1743G>C as compared to c.1742A>G. This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;.;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Uncertain	2.0	.;M;M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;.
REVEL	Uncertain	0.48
Sift	Benign	0.042	D;D;D;D;.
Sift4G	Uncertain	0.057	T;D;D;T;T
Polyphen		0.97	.;D;D;.;.
Vest4		0.70, 0.61
MutPred		0.48		.;Loss of ubiquitination at K581 (P = 0.027);Loss of ubiquitination at K581 (P = 0.027);Loss of ubiquitination at K581 (P = 0.027);.;
MVP		0.59
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1114167592; hg19: chr5-112164669;