5-112792505-A-G

Variant names:

• chr5-112792505-A-G
• rs147036141
• NM_000038.6:c.705A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP7 BS2 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The c.705A>G (p.Leu235=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant has been observed 3 (≥ 2) times in homozygous state in gnomAD 2.1.1 (BS2). The highest population minor allele frequency in the non-cancer population of gnomAD v2.1.1 is 0.004669 in the Finnish population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (>0.001) 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, BS2, BP4, and BP7 (Specification Version 1.0; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA012805/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (10 hom.)
• Consequence: APC NM_001354906.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:25
• Conservation: PhyloP100: 0.616
• Publications: 7 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 -14 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.
• BS2: 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_001354906.2. 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.705A>G	p.Leu235Leu	synonymous	Exon 7 of 16	NP_000029.2
	APC	NM_001354906.2		c.-331A>G		5_prime_UTR_premature_start_codon_gain	Exon 7 of 17	NP_001341835.1
	APC	NM_001407470.1		c.-331A>G		5_prime_UTR_premature_start_codon_gain	Exon 7 of 17	NP_001394399.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.705A>G	p.Leu235Leu	synonymous	Exon 7 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.705A>G	p.Leu235Leu	synonymous	Exon 8 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.705A>G		non_coding_transcript_exon	Exon 6 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 322 AN: 152248 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00228 AC: 573 AN: 251210 AF XY: 0.00219

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00318 AC: 4649 AN: 1460340 Hom.: 10 Cov.: 29 AF XY: 0.00304 AC XY: 2209 AN XY: 726514

African (AFR) AF: 0.000509 AC: 17 AN: 33428

American (AMR) AF: 0.00170 AC: 76 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86186

European-Finnish (FIN) AF: 0.000676 AC: 36 AN: 53262

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5750

European-Non Finnish (NFE) AF: 0.00380 AC: 4220 AN: 1111136

Other (OTH) AF: 0.00260 AC: 157 AN: 60292

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152366 Hom.: 3 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74524

African (AFR) AF: 0.000457 AC: 19 AN: 41592

American (AMR) AF: 0.00327 AC: 50 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00329 Hom.: 1

Bravo AF: 0.00230

Asia WGS AF: 0.000868 AC: 3 AN: 3472

EpiCase AF: 0.00443

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	7	not specified (7)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	Familial adenomatous polyposis 1 (4)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.8
DANN	Benign	0.80
PhyloP100		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs147036141; hg19: chr5-112128202;