rs1114167603

Positions:

• chr5-112838671-A-C
• chr5-112838671-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM5_Supporting PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3077A>C variant in APC is a missense variant predicted to cause the substitution of asparagine by threonine at amino acid position 1026 (p.Asn1026Thr). This variant has been reported in 3 probands with FAP worth 1.5 phenotype points (PS4_Supporting; Ambry Internal Data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.3077A>G (p.Asn1026Ser) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting; PMID 18166348). In summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PS4_Supporting, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16028070/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 8.72

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.
• PM5: 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.3077A>C	p.Asn1026Thr	missense_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3077A>C	p.Asn1026Thr	missense_variant	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:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2016

The p.N1026T variant (also known as c.3077A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 3077. The asparagine at codon 1026 is replaced by threonine, an amino acid with similar properties. While this exact alteration has not been reported in the literature to our knowledge, a similar alteration at this same location, p.N1026S (c.3077A>G), has been reported to segregate with disease in a large Spanish attenuated FAP family (Menéndez M et al. Gastroenterology 2008 Jan; 134(1):56-64). Menéndez M et al. further investigated the functional significance of the p.N1026S alteration using an in vitro beta-catenin binding assay and showed it resulted in a functionally altered protein. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Asn1026Thr was not identified in the literature, dbSNP, 1000 Genomes Project, NHLBI GO Exome Sequencing Project (ESP, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015), Clinvitae database, COSMIC, Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, the InSiGHT Colon Cancer Gene Variant Database (LOVD) and UMD. A variant at the same loci, p.Asn1026Ser was identified in the literature and classified as pathogenic based on segregation data and in vivo studies (Menendez 2008). The p.Asn1026 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Feb 25, 2023

The c.3077A>C variant in APC is a missense variant predicted to cause the substitution of asparagine by threonine at amino acid position 1026 (p.Asn1026Thr). This variant has been reported in 3 probands with FAP worth 1.5 phenotype points (PS4_Supporting; Ambry Internal Data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.3077A>G (p.Asn1026Ser) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting; PMID 18166348). In summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PS4_Supporting, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.55	.;N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Benign	0.34	T;D;D;T
Polyphen		1.0	.;D;D;.
Vest4		0.88, 0.79
MutPred		0.72		.;Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.89
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.59

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: rs1114167603; hg19: chr5-112174368;