5-112843456-C-G

Variant names:

• chr5-112843456-C-G
• rs72541816
• NM_000038.6:c.7862C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS2 BA1 BP1

This summary comes from the ClinGen Evidence Repository: The c.7862C>G variant in APC is a missense variant predicted to cause the substitution of Serine by Cysteine at amino acid position 2621 (p.Ser2621Cys). This variant has been observed in more than 10 heterozygous individuals over the age of 50 with no features of FAP, worth more than 10 healthy individual points (BS2; Ambry internal data). APC is defined by the ClinGen APC VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.5021% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold of 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 ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BA1, BS2, and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA014123/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (22 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign reviewed by expert panel B:24 O:1
• Conservation: PhyloP100: 4.73
• Publications: 29 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

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP1: 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_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.7862C>G	p.Ser2621Cys	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.7946C>G	p.Ser2649Cys	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.7916C>G	p.Ser2639Cys	missense	Exon 17 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.7862C>G	p.Ser2621Cys	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.7862C>G	p.Ser2621Cys	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-13193C>G		intron	N/A	ENSP00000454861.1	H3BNH8

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00291 AC: 727 AN: 249960 AF XY: 0.00290

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00475 AC: 6949 AN: 1461508 Hom.: 22 Cov.: 34 AF XY: 0.00468 AC XY: 3401 AN XY: 727070

African (AFR) AF: 0.000777 AC: 26 AN: 33464

American (AMR) AF: 0.000738 AC: 33 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00229 AC: 197 AN: 86198

European-Finnish (FIN) AF: 0.00197 AC: 105 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00572 AC: 6356 AN: 1111754

Other (OTH) AF: 0.00348 AC: 210 AN: 60382

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74468

African (AFR) AF: 0.00132 AC: 55 AN: 41562

American (AMR) AF: 0.00216 AC: 33 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00551 AC: 375 AN: 68020

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00460 Hom.: 2

Bravo AF: 0.00320

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00312 AC: 379

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00451

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	Familial adenomatous polyposis 1 (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not specified (6)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.31
Sift	Benign	0.037	D
Sift4G	Uncertain	0.031	D
Polyphen		0.64	P
Vest4		0.30
MVP		0.74
ClinPred		0.014	T
GERP RS		6.1
Varity_R		0.075
gMVP		0.50
Mutation Taster		=96/4	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: rs72541816; hg19: chr5-112179153; COSMIC: COSV99078827; COSMIC: COSV99078827;