rs876660174

Variant names:

• chr5-112841648-AGTTT-A
• rs876660174
• NM_000038.6:c.6059_6062delGTTT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.6059_6062delGTTT​(p.Cys2020SerfsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C2020C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.60
• 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: 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 263 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112841648-AGTTT-A is Pathogenic according to our data. Variant chr5-112841648-AGTTT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 233077.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.6059_6062delGTTT	p.Cys2020SerfsTer23	frameshift	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.6143_6146delGTTT	p.Cys2048SerfsTer23	frameshift	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.6113_6116delGTTT	p.Cys2038SerfsTer23	frameshift	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.6059_6062delGTTT	p.Cys2020SerfsTer23	frameshift	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.6059_6062delGTTT	p.Cys2020SerfsTer23	frameshift	Exon 17 of 17	ENSP00000427089.2
	APC	ENST00000508624.5	TSL:1	n.*5381_*5384delGTTT		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 06, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of 4 nucleotides in APC is denoted c.6059_6062delGTTT at the cDNA level and p.Cys2020SerfsX23 (C2020SfsX23) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GTTT[delGTTT]CTCA. The deletion causes a frameshift which changes a Cysteine to a Serine at codon 2020, and creates a premature stop codon at position 23 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 824 amino acids are replaced by 22 incorrect amino acids and is predicted to cause loss of normal protein function through protein truncation, resulting in the loss of several functional domains (Azzopardi 2008). This variant has not, to our knowledge, been reported in the literature. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.

Familial adenomatous polyposis 1 Pathogenic:1

Jun 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys2020Serfs*23) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 824 amino acid(s) of the APC protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the APC protein. Other variant(s) that disrupt this region (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 233077). This variant is not present in population databases (ExAC no frequency).

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 23, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6059_6062delGTTT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides between nucleotide positions 6059 and 6062, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs876660174; hg19: chr5-112177345; COSMIC: COSV57341768; COSMIC: COSV57341768;