rs1554069570

Variant names:

• chr5-112766411-G-A
• rs1554069570
• NM_000038.6:c.220+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112766411-G-A
• chr5-112766411-G-T
• chr5-112766411-G-C

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.220+1G>A variant in APC occurs within the canonical splice donor site (+1) of intron 3. It is predicted to cause skipping of exon 3, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1). This prediction is confirmed by RNA analysis (internal data from Ambry Genetics and Invitae). This variant has been reported in one family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, [internal data from Ambry Genetics]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA360617465/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 8.68
• Publications: 0 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.220+1G>A		splice_donor intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.250+1G>A		splice_donor intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.220+1G>A		splice_donor intron	N/A	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.220+1G>A		splice_donor intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.220+1G>A		splice_donor intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.220+1G>A		splice_donor intron	N/A	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Familial adenomatous polyposis 1 (4)
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	Uncertain	0.050
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.7
GERP RS		4.8
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: 14
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs1554069570; hg19: chr5-112102108;