5-112838671-A-G

Position:

chr5-112838671-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_SupportingPS4_ModeratePP1_StrongPS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3077A>G variant in APC is a missense variant predicted to cause the substitution of asparagine by serine at amino acid position 1026 (p.Asn1026Ser). This variant has been reported to segregate with FAP in ≥ 7 meioses in 2 families (PP1_strong; PMID 18166348, Barcelona internal data). Increased β-catenin regulated transcription activity and decreased binding to β-catenin by surface plasmon resonance are also demonstrated (PS3_Supporting; PMID18166348). This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 3.5 points (PS4_Moderate, PMID 18166348, Invitae and Barcelona Internal data). Finally, 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 FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PP1_Strong, PS4_Moderate, PS3_Supporting, and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16028071/MONDO:0021056/089

Frequency

Genomes: not found (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:3

Conservation

PhyloP100: 8.72

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS3

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.

PP1

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 linkuse as main transcript	c.3077A>G	p.Asn1026Ser	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 linkuse as main transcript	c.3077A>G	p.Asn1026Ser	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727220

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 25, 2023	The c.3077A>G variant in APC is a missense variant predicted to cause the substitution of asparagine by serine at amino acid position 1026 (p.Asn1026Ser). This variant has been reported to segregate with FAP in more than 7 meioses in 2 families (PP1_strong; PMID 18166348, Barcelona internal data). Increased beta-catenin regulated transcription activity and decreased binding to beta-catenin by surface plasmon resonance are also demonstrated (PS3_Supporting; PMID18166348). This variant has been reported in 2 families meeting phenotypic criteria, resulting in a total phenotype score of 3.5 points (PS4_Moderate, PMID 18166348, Invitae and Barcelona Internal data). Finally, 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 FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PP1_Strong, PS4_Moderate, PS3_Supporting, and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 04, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APC function (PMID: 18166348). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. ClinVar contains an entry for this variant (Variation ID: 1393312). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (AFAP) (PMID: 18166348). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1026 of the APC protein (p.Asn1026Ser). -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The p.N1026S variant (also known as c.3077A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3077. The asparagine at codon 1026 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in the literature to segregate with disease in a family affected with attenuated familial adenomatous polyposis (AFAP) (Menéndez M et al. Gastroenterology, 2008 Jan;134:56-64). In addition, functional studies indicated that the variant impaired binding to beta-catenin and resulted in increased beta-catenin-regulated transcriptional activity (Menéndez M et al. Gastroenterology, 2008 Jan;134:56-64). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

0.92

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D;D;D

Eigen

Uncertain

0.59

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

0.55

.;N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.79

N;N;N;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Benign

0.46

T;T;T;T

Polyphen

1.0

.;D;D;.

Vest4

0.93, 0.77

MutPred

0.87

.;Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.89

ClinPred

0.74

GERP RS

5.8

Varity_R

0.59

gMVP

0.58

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over