5-112775612-TAAA-TAA

Variant names:

• chr5-112775612-TA-T
• rs730881230
• NM_000038.6:c.423-4delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.423-4del variant in APC is an intronic variant which results in the deletion of adenine at position -4 of intron 4. The highest allele frequency is 5.48% in gnomAD v3.1.2, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold for BA1 (≥ 0.1%). RNA assays showed no splicing mutation, indicating that this variant does not impact protein function (BS3_Supporting; PMID22447671). Finally, the results from ≥2 in silico splicing predictors support that this variant does not affect splicing (BP4). 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, BS3_Supporting, BP4. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CV181781/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.018 (70 hom., cov: 32)
  • Exomes 𝑓: 0.18 (13 hom.)
• Consequence: APC NM_000038.6 splice_region, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:18
• Conservation: PhyloP100: -0.937
• Publications: 4 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

ACMG classification

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

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.423-4delA		splice_region intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.453-4delA		splice_region intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.423-4delA		splice_region intron	N/A	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.423-16delA		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.423-16delA		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.423-16delA		intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2623 AN: 143400 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00418

Gnomad EAS AF: 0.00239

Gnomad SAS AF: 0.00984

Gnomad FIN AF: 0.00738

Gnomad MID AF: 0.00676

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.253 AC: 25644 AN: 101416 AF XY: 0.259

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.297

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.182 AC: 155333 AN: 853448 Hom.: 13 Cov.: 0 AF XY: 0.185 AC XY: 78147 AN XY: 422492

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.232 AC: 4772 AN: 20558

American (AMR) AF: 0.207 AC: 5500 AN: 26586

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 3451 AN: 14880

East Asian (EAS) AF: 0.217 AC: 4787 AN: 22060

South Asian (SAS) AF: 0.228 AC: 11176 AN: 49080

European-Finnish (FIN) AF: 0.175 AC: 5436 AN: 31000

Middle Eastern (MID) AF: 0.147 AC: 499 AN: 3390

European-Non Finnish (NFE) AF: 0.173 AC: 112792 AN: 650654

Other (OTH) AF: 0.196 AC: 6920 AN: 35240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0183 AC: 2631 AN: 143460 Hom.: 70 Cov.: 32 AF XY: 0.0183 AC XY: 1276 AN XY: 69562

African (AFR) AF: 0.0549 AC: 2165 AN: 39466

American (AMR) AF: 0.00725 AC: 104 AN: 14344

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 14 AN: 3348

East Asian (EAS) AF: 0.00240 AC: 12 AN: 5004

South Asian (SAS) AF: 0.00987 AC: 45 AN: 4560

European-Finnish (FIN) AF: 0.00738 AC: 62 AN: 8404

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.00285 AC: 186 AN: 65208

Other (OTH) AF: 0.0208 AC: 41 AN: 1972

Alfa AF: 0.0864 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	1	APC-related disorder (1)
-	-	1	Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism

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: rs730881230; hg19: chr5-112111309; COSMIC: COSV57396815; COSMIC: COSV57396815;