5-112767263-C-T

Variant names:

• chr5-112767263-C-T
• rs139196838
• NM_000038.6:c.295C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP5 BS1 BS2 BP1 BP2

This summary comes from the ClinGen Evidence Repository: The c.295C>T variant in APC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid position 99 (p.Arg99Trp). 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 of the variant c.295C>T in gnomAD v2.1.1 (non-cancer) is 0.0007355 (95/129170 alleles) in the European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1 (BS1). This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae and Ambry Genetics internal data). It has also been observed once in a homozygous state (Ambry Genetics internal data). This variant has been observed 4 times with other APC variants deemed (likely) pathogenic by the HCCP VCEP in individuals with FAP (BP2; PMIDs 23159591, 25604157, Bonn internal data). Finally, this variant has been observed in 6 patients with an alternate molecular basis for disease (BP5; Leiden University Medical Center internal data). 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: BS1, BS2, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007948/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: APC NM_001354906.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:7 B:17
• Conservation: PhyloP100: 1.59
• Publications: 36 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 -11 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.295C>T	p.Arg99Trp	missense	Exon 4 of 16	NP_000029.2
	APC	NM_001354906.2		c.-741C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 17	NP_001341835.1
	APC	NM_001407470.1		c.-741C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 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.295C>T	p.Arg99Trp	missense	Exon 4 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.295C>T	p.Arg99Trp	missense	Exon 5 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.295C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000394 AC: 99 AN: 251458 AF XY: 0.000405

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000815 AC: 1191 AN: 1461846 Hom.: 1 Cov.: 31 AF XY: 0.000822 AC XY: 598 AN XY: 727230

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00102 AC: 1132 AN: 1111992

Other (OTH) AF: 0.000778 AC: 47 AN: 60392

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74280

African (AFR) AF: 0.000459 AC: 19 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000682 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000872

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	5	Familial adenomatous polyposis 1 (7)
-	2	3	not provided (5)
-	2	3	not specified (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	APC-related disorder (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Classic or attenuated familial adenomatous polyposis (1)
-	1	-	Colorectal cancer, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.94
ClinPred		0.13	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.30
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.030		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: rs139196838; hg19: chr5-112102960; COSMIC: COSV57367627; COSMIC: COSV57367627;