5-112841059-T-A

Variant names:

• chr5-112841059-T-A
• rs459552
• NM_000038.6:c.5465T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP1

This summary comes from the ClinGen Evidence Repository: The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC 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 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010422/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.82 (51880 hom., cov: 31)
  • Exomes 𝑓: 0.78 (441782 hom.)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Benign reviewed by expert panel B:23 O:3
• Conservation: PhyloP100: 2.36
• Publications: 190 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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 -9 ACMG points.

• BP1: 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_001407446.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.5465T>A	p.Val1822Asp	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.5549T>A	p.Val1850Asp	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.5519T>A	p.Val1840Asp	missense	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.5465T>A	p.Val1822Asp	missense	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.5465T>A	p.Val1822Asp	missense	Exon 17 of 17	ENSP00000427089.2
	APC	ENST00000508624.5	TSL:1	n.*4787T>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124670 AN: 152042 Hom.: 51821 Cov.: 31

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.816

GnomAD2 exomes AF: 0.795 AC: 199083 AN: 250474 AF XY: 0.789

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.766

Gnomad EAS exome AF: 0.903

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.777 AC: 1133202 AN: 1459012 Hom.: 441782 Cov.: 53 AF XY: 0.776 AC XY: 563110 AN XY: 725998

African (AFR) AF: 0.961 AC: 32111 AN: 33408

American (AMR) AF: 0.827 AC: 36984 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 20005 AN: 26112

East Asian (EAS) AF: 0.904 AC: 35881 AN: 39672

South Asian (SAS) AF: 0.779 AC: 67182 AN: 86204

European-Finnish (FIN) AF: 0.695 AC: 37090 AN: 53394

Middle Eastern (MID) AF: 0.788 AC: 4543 AN: 5764

European-Non Finnish (NFE) AF: 0.768 AC: 851815 AN: 1109448

Other (OTH) AF: 0.789 AC: 47591 AN: 60314

GnomAD4 genome AF: 0.820 AC: 124789 AN: 152160 Hom.: 51880 Cov.: 31 AF XY: 0.816 AC XY: 60692 AN XY: 74374

African (AFR) AF: 0.957 AC: 39732 AN: 41534

American (AMR) AF: 0.812 AC: 12422 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2640 AN: 3468

East Asian (EAS) AF: 0.902 AC: 4677 AN: 5184

South Asian (SAS) AF: 0.793 AC: 3823 AN: 4818

European-Finnish (FIN) AF: 0.669 AC: 7073 AN: 10572

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51747 AN: 67970

Other (OTH) AF: 0.815 AC: 1720 AN: 2110

Alfa AF: 0.779 Hom.: 28582

Bravo AF: 0.841

TwinsUK AF: 0.759 AC: 2814

ALSPAC AF: 0.778 AC: 3000

ESP6500AA AF: 0.946 AC: 4164

ESP6500EA AF: 0.765 AC: 6579

ExAC AF: 0.798 AC: 96838

Asia WGS AF: 0.856 AC: 2975 AN: 3478

EpiCase AF: 0.764

EpiControl AF: 0.775

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	Familial adenomatous polyposis 1 (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Classic or attenuated familial adenomatous polyposis (1)
-	-	1	Familial multiple polyposis syndrome (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.19
Sift	Benign	0.67	T
Sift4G	Benign	0.082	T
Polyphen		0.0	B
Vest4		0.031
ClinPred		0.0020	T
GERP RS		3.6
Varity_R		0.084
gMVP		0.28
Mutation Taster		=98/2	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: rs459552; hg19: chr5-112176756; COSMIC: COSV57321643; COSMIC: COSV57321643;