Genetic Variant APC:p.Glu1157del (chr5-112839053-TGAA-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_000038.6(APC):c.3468_3470delAGA(p.Glu1157del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,614,062 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1156E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 5 hom. )

Consequence

APC
NM_000038.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:26

Conservation

PhyloP100: 7.96

Publications

7 publications found

Variant links:

COSMIC-nc: COSV57372123

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 Gene-Disease associations (from GenCC):

classic or attenuated familial adenomatous polyposis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
desmoid tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
familial adenomatous polyposis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
gastric adenocarcinoma and proximal polyposis of the stomach
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
APC-related attenuated familial adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Turcot syndrome with polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000038.6

BP6

Variant 5-112839053-TGAA-T is Benign according to our data. Variant chr5-112839053-TGAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00393 (599/152262) while in subpopulation AFR AF = 0.0138 (574/41558). AF 95% confidence interval is 0.0129. There are 6 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APC	NM_000038.6	MANE Select	c.3468_3470delAGA	p.Glu1157del	disruptive_inframe_deletion	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.3552_3554delAGA	p.Glu1185del	disruptive_inframe_deletion	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.3522_3524delAGA	p.Glu1175del	disruptive_inframe_deletion	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APC	ENST00000257430.9	TSL:5 MANE Select	c.3468_3470delAGA	p.Glu1157del	disruptive_inframe_deletion	Exon 16 of 16	ENSP00000257430.4	P25054-1
APC	ENST00000508376.6	TSL:1	c.3468_3470delAGA	p.Glu1157del	disruptive_inframe_deletion	Exon 17 of 17	ENSP00000427089.2	P25054-1
APC	ENST00000502371.3	TSL:1	n.1666_1668delAGA		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00101

AC:

253

AN:

250976

AF XY:

0.000818

show subpopulations

Gnomad AFR exome

AF:

0.0128

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000970

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000506

AC:

740

AN:

1461800

Hom.:

AF XY:

0.000435

AC XY:

316

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0150

AC:

502

AN:

33478

American (AMR)

AF:

0.000716

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000130

AC:

145

AN:

1111994

Other (OTH)

AF:

0.000878

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00393

AC:

599

AN:

152262

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

284

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0138

AC:

574

AN:

41558

American (AMR)

AF:

0.000458

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68018

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000679

Hom.:

Bravo

AF:

0.00444

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (6)

Familial adenomatous polyposis 1 (5)

Hereditary cancer-predisposing syndrome (5)

APC-Associated Polyposis Disorders (1)

Classic or attenuated familial adenomatous polyposis (1)

Desmoid disease, hereditary;C2713442:Familial adenomatous polyposis 1 (1)

Familial multiple polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over