rs1060503328

Variant names:

• chr5-112775677-G-A
• rs1060503328
• NM_000038.6:c.471G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112775677-G-A
• chr5-112775677-G-C
• chr5-112775677-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.471G>A (p.Trp157Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 5 in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/233100 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in 1 proband meeting phenotypic criteria, resulting in a total phenotype score of 1.0 (PS4_Supporting, PMID:20399906). Moreover, the variant has been reported in at least 4 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID:22941256, 8381580, 20685668; ClinVar ID: VCV000411479.17). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications version 2.0.3; date of approval: 7/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16022351/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.20
• Publications: 3 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.471G>A	p.Trp157*	stop_gained	Exon 5 of 16	NP_000029.2
	APC	NM_001407446.1		c.501G>A	p.Trp167*	stop_gained	Exon 4 of 16	NP_001394375.1
	APC	NM_001354896.2		c.471G>A	p.Trp157*	stop_gained	Exon 5 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.471G>A	p.Trp157*	stop_gained	Exon 5 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.471G>A	p.Trp157*	stop_gained	Exon 6 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.471G>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247596 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456216 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724158

African (AFR) AF: 0.00 AC: 0 AN: 33210

American (AMR) AF: 0.00 AC: 0 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 84456

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109670

Other (OTH) AF: 0.00 AC: 0 AN: 60172

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Familial adenomatous polyposis 1 (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.2
Vest4		0.94
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1060503328; hg19: chr5-112111374; COSMIC: COSV104379174;