5-112838682-A-T

Variant names:

• chr5-112838682-A-T
• rs587779786
• NM_000038.6:c.3088A>T

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.3088A>T​(p.Lys1030*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.72
• Publications: 9 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 1189 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838682-A-T is Pathogenic according to our data. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838682-A-T is described in CliVar as Pathogenic. Clinvar id is 127284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3088A>T	p.Lys1030*	stop_gained	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3088A>T	p.Lys1030*	stop_gained	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+9710A>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 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: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 30, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a nonsense variant, denoted APC c.3088A>T at the cDNA level and p.Lys1030Ter (K1030X) at the protein level. The substitution creates a nonsense variant, changing a Lysine to a premature stop codon (AAA>TAA). This variant is predicted to cause loss of normal protein function through protein truncation. Although, this variant has not, to our knowledge, been published in the literature, there are multiple other reports of pathogenic nonsense variants upstream and downstream of this mutation per HGMD. -

Jul 17, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Pathogenic:1

Nov 08, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A different truncation (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 deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. This variant has been observed in individual(s) with polyposis (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127284). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Lys1030*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1814 amino acids of the APC protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.7
Vest4		0.99, 0.96
GERP RS		5.8
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: rs587779786; hg19: chr5-112174379; COSMIC: COSV57334397; COSMIC: COSV57334397;