5-112839993-C-T

Variant names:

• chr5-112839993-C-T
• rs749142480
• NM_000038.6:c.4399C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP5 BS1 BS2 BS3_Supporting BP1

This summary comes from the ClinGen Evidence Repository: The c.4399C>T variant in APC is a missense variant predicted to cause the substitution of Proline by Serine at amino acid position 1467 (p.Pro1467Ser). 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). This variant has been observed in a heterozygous state in 75 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data). In addition, it has also been observed in 1 patient with an alternate molecular basis for disease – a pathogenic MSH6 germline variant (BP5; Melbourne Internal data). Functional study of β-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as the wild type (BS3_Supporting; PMID:18199528). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1). 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, BS3_Supporting, BP1 and BP5 (VCEP Specification version 1, date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA038968/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign reviewed by expert panel U:9 B:2
• Conservation: PhyloP100: 3.33
• Publications: 11 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 -11 ACMG points.

• BP1: 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.
• BS3: 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.4399C>T	p.Pro1467Ser	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.4483C>T	p.Pro1495Ser	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.4453C>T	p.Pro1485Ser	missense	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.4399C>T	p.Pro1467Ser	missense	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.4399C>T	p.Pro1467Ser	missense	Exon 17 of 17	ENSP00000427089.2
	APC	ENST00000508624.5	TSL:1	n.*3721C>T		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251166 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 727242

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	1	Familial adenomatous polyposis 1 (4)
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	2	-	not provided (2)
-	1	-	Classic or attenuated familial adenomatous polyposis (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
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.55
Sift	Benign	0.23	T
Sift4G	Benign	0.66	T
Polyphen		0.44	B
Vest4		0.69
MutPred		0.72		Loss of helix (P = 0.0076)
MVP		0.98
ClinPred		0.098	T
GERP RS		5.3
Varity_R		0.051
gMVP		0.68
Mutation Taster		=1/99	disease causing

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: rs749142480; hg19: chr5-112175690;