5-112838677-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS4PM5_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3083G>T variant in APC is a missense variant predicted to cause the substitution of serine by isoleucine at amino acid position 1028 (p.Ser1028Ile). This variant has been reported in 6 individuals resulting in a total phenotype score of 4.5 (PS4, Ambry, Invitae, Melbourne internal data). Another missense variant c.3084T>A (p.Ser1028Arg) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Splicing prediction using SpliceAI and varSEAK revealed no expected effects on splicing due to any of these variants. Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16028086/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:2U:3

Conservation

PhyloP100: 9.36

Variant links:

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 links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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 rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.3083G>T	p.Ser1028Ile	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 link	c.3083G>T	p.Ser1028Ile	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+9705G>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Pathogenic:1Uncertain:1

Feb 25, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.3083G>T variant in APC is a missense variant predicted to cause the substitution of serine by isoleucine at amino acid position 1028 (p.Ser1028Ile). This variant has been reported in 6 individuals resulting in a total phenotype score of 4.5 (PS4, Ambry, Invitae, Melbourne internal data). Another missense variant c.3084T>A (p.Ser1028Arg) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Splicing prediction using SpliceAI and varSEAK revealed no expected effects on splicing due to any of these variants. Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). -

Jul 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with isoleucine at codon 1028 of the APC protein (p.Ser1028Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -

not provided

Uncertain:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

May 19, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1028I variant (also known as c.3083G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 3083. The serine at codon 1028 is replaced by isoleucine, an amino acid with dissimilar properties. Another likely pathogenic variant at the same nucleotide position, p.S1028N (c.3083G>A), has segregated with disease in a family with attenuated familial adenomatous polyposis (AFAP) and colorectal cancer (Ambry internal data). In addition, internal structural analysis for the p.S1028N variant indicated that this lies on the protein interface important for β-Catenin binding (Ambry internal data). The p.S1028I 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D;D;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.69

.;N;N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.7

D;N;N;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.96, 0.85

MutPred

0.67

.;Loss of disorder (P = 0.0056);Loss of disorder (P = 0.0056);Loss of disorder (P = 0.0056);

MVP

1.0

ClinPred

0.97

GERP RS

5.8

Varity_R

0.90

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over