rs1554082152

Variant names:

• chr5-112828986-CATTTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATT-C
• rs1554082152
• NM_000038.6:c.1743+18_1743+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000038.6(APC):​c.1743+18_1743+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,539,288 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• Publications: 1 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 -8 ACMG points.

• BP6: Variant 5-112828986-CATTTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATT-C is Benign according to our data. Variant chr5-112828986-CATTTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 422230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1743+18_1743+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT		intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.1827+18_1827+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT		intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.1797+18_1797+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT		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.1743+18_1743+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT		intron	N/A	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.1743+18_1743+106delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT		intron	N/A	ENSP00000427089.2	P25054-1
	APC	ENST00000505084.2	TSL:1	n.1817_1905delTAGTACTATAATATGAATTTCATGTTTGGCTTTTTTTTGCTGCCTTCTTTTAGCCATGAGATTTCCTAATTTCTTACCTGTGTATTATT		non_coding_transcript_exon	Exon 14 of 14

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250982 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 27 AN: 1387082 Hom.: 1 AF XY: 0.0000173 AC XY: 12 AN XY: 694442

African (AFR) AF: 0.00 AC: 0 AN: 31934

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25708

East Asian (EAS) AF: 0.000612 AC: 24 AN: 39238

South Asian (SAS) AF: 0.00 AC: 0 AN: 84694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044140

Other (OTH) AF: 0.0000518 AC: 3 AN: 57900

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74418

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41506

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1554082152; hg19: chr5-112164683;