dbSNP rs2229993: APC:p.Ser2307Ser (chr5-112842515-G-A) – 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.6921G>A(p.Ser2307Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,912 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2307S) has been classified as Likely benign. The gene APC is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25

Conservation

PhyloP100: -0.254

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104567403

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

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 5-112842515-G-A is Benign according to our data. Variant chr5-112842515-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.254 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00135 (206/152162) while in subpopulation NFE AF = 0.00235 (160/67990). AF 95% confidence interval is 0.00206. There are 1 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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.6921G>A	p.Ser2307Ser	synonymous	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.7005G>A	p.Ser2335Ser	synonymous	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.6975G>A	p.Ser2325Ser	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.6921G>A	p.Ser2307Ser	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
APC	ENST00000508376.6	TSL:1	c.6921G>A	p.Ser2307Ser	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
APC	ENST00000508624.5	TSL:1	n.*6243G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00145

AC:

364

AN:

250966

AF XY:

0.00143

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00220

AC:

3211

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1550

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33468

American (AMR)

AF:

0.000626

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000104

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00264

AC:

2933

AN:

1111932

Other (OTH)

AF:

0.00224

AC:

135

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

191

382

573

764

955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.00135

AC:

206

AN:

152162

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41516

American (AMR)

AF:

0.000458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000849

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

67990

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

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:

0.00184

Hom.:

Bravo

AF:

0.00155

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

not specified (8)

Hereditary cancer-predisposing syndrome (5)

Familial adenomatous polyposis 1 (2)

APC-Associated Polyposis Disorders (1)

Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.6

(source)

DANN

Benign

0.76

PhyloP100

-0.25

Mutation Taster

=100/0

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