Genetic Variant APC:p.Leu2401Leu (chr5-112842795-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000038.6(APC):c.7201C>T(p.Leu2401Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,613,536 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2401L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 8 hom., cov: 32)

Exomes 𝑓: 0.013 ( 166 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:25

Conservation

PhyloP100: 3.42

Publications

15 publications found

Variant links:

COSMIC-nc: COSV57322843

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 5-112842795-C-T is Benign according to our data. Variant chr5-112842795-C-T is described in ClinVar as Benign. ClinVar VariationId is 42249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.41 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0111 (1696/152246) while in subpopulation AMR AF = 0.017 (260/15296). AF 95% confidence interval is 0.0153. There are 8 homozygotes in GnomAd4. There are 816 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.7201C>T	p.Leu2401Leu	synonymous	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.7285C>T	p.Leu2429Leu	synonymous	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.7255C>T	p.Leu2419Leu	synonymous	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.7201C>T	p.Leu2401Leu	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
APC	ENST00000508376.6	TSL:1	c.7201C>T	p.Leu2401Leu	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
ENSG00000258864	ENST00000520401.1	TSL:3	n.228+13823C>T		intron	N/A	ENSP00000454861.1	H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1696

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00860

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0170

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0101

AC:

2514

AN:

250140

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.00808

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0128

AC:

18702

AN:

1461290

Hom.:

166

Cov.:

AF XY:

0.0125

AC XY:

9072

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00899

AC:

301

AN:

33468

American (AMR)

AF:

0.0119

AC:

532

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0229

AC:

599

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00231

AC:

199

AN:

86242

European-Finnish (FIN)

AF:

0.00193

AC:

103

AN:

53378

Middle Eastern (MID)

AF:

0.0192

AC:

111

AN:

5768

European-Non Finnish (NFE)

AF:

0.0145

AC:

16083

AN:

1111518

Other (OTH)

AF:

0.0128

AC:

773

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1047

2094

3142

4189

5236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<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:

0.0111

AC:

1696

AN:

152246

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

816

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00862

AC:

358

AN:

41540

American (AMR)

AF:

0.0170

AC:

260

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

916

AN:

68012

Other (OTH)

AF:

0.0138

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0132

Hom.:

Bravo

AF:

0.0124

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0155

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Hereditary cancer-predisposing syndrome (5)

not provided (4)

Familial adenomatous polyposis 1 (3)

APC-Associated Polyposis Disorders (1)

Carcinoma of colon (1)

Classic or attenuated familial adenomatous polyposis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.6

(source)

DANN

Benign

0.65

PhyloP100

3.4

Mutation Taster

=97/3

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