rs2229992

Variant names:

• chr5-112827157-T-C
• rs2229992
• NM_000038.6:c.1458T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-112827157-T-C
• chr5-112827157-T-G
• chr5-112827157-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005169/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.48 (20030 hom., cov: 32)
  • Exomes 𝑓: 0.59 (255569 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign reviewed by expert panel B:23 O:1
• Conservation: PhyloP100: 1.30
• Publications: 100 publications found

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

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.1458T>C	p.Tyr486Tyr	synonymous	Exon 12 of 16	NP_000029.2
	APC	NM_001407446.1		c.1542T>C	p.Tyr514Tyr	synonymous	Exon 12 of 16	NP_001394375.1
	APC	NM_001354896.2		c.1512T>C	p.Tyr504Tyr	synonymous	Exon 13 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1458T>C	p.Tyr486Tyr	synonymous	Exon 12 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1458T>C	p.Tyr486Tyr	synonymous	Exon 13 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000505084.2	TSL:1	n.1514T>C		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73262 AN: 151924 Hom.: 20034 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.584 AC: 146698 AN: 251038 AF XY: 0.588

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.698

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.673

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.592

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.587 AC: 857202 AN: 1460910 Hom.: 255569 Cov.: 41 AF XY: 0.589 AC XY: 428012 AN XY: 726798

African (AFR) AF: 0.189 AC: 6320 AN: 33450

American (AMR) AF: 0.690 AC: 30819 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 14731 AN: 26116

East Asian (EAS) AF: 0.713 AC: 28248 AN: 39642

South Asian (SAS) AF: 0.638 AC: 55060 AN: 86240

European-Finnish (FIN) AF: 0.517 AC: 27573 AN: 53366

Middle Eastern (MID) AF: 0.553 AC: 3183 AN: 5760

European-Non Finnish (NFE) AF: 0.591 AC: 656712 AN: 1111288

Other (OTH) AF: 0.573 AC: 34556 AN: 60354

GnomAD4 genome AF: 0.482 AC: 73275 AN: 152042 Hom.: 20030 Cov.: 32 AF XY: 0.485 AC XY: 36041 AN XY: 74300

African (AFR) AF: 0.206 AC: 8558 AN: 41488

American (AMR) AF: 0.623 AC: 9515 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1905 AN: 3466

East Asian (EAS) AF: 0.671 AC: 3470 AN: 5172

South Asian (SAS) AF: 0.646 AC: 3116 AN: 4822

European-Finnish (FIN) AF: 0.481 AC: 5067 AN: 10544

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39818 AN: 67956

Other (OTH) AF: 0.512 AC: 1079 AN: 2106

Alfa AF: 0.528 Hom.: 20633

Bravo AF: 0.483

Asia WGS AF: 0.600 AC: 2085 AN: 3478

EpiCase AF: 0.584

EpiControl AF: 0.587

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	2	not provided (2)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.1
DANN	Benign	0.78
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229992; hg19: chr5-112162854; COSMIC: COSV57321592; COSMIC: COSV57321592;