rs587782557

chr5-112775631-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):c.426_427del(p.Leu143AlafsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S142S) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112775631-CAT-C is Pathogenic according to our data. Variant chr5-112775631-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 142574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112775631-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.426_427del	p.Leu143AlafsTer4	frameshift_variant	5/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.426_427del	p.Leu143AlafsTer4	frameshift_variant	5/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425600 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 709996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Leu143Alafs*4) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pilomatrixomas and attenuated familial adenomatous polyposis (PMID: 8252630, 11960572, 15300576, 18063416, 22150579, 23159591). ClinVar contains an entry for this variant (Variation ID: 142574). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 25, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 13, 2023	PP1, PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2016	This deletion of 2 nucleotides in APC is denoted c.426_427delAT at the cDNA level and p.Leu143AlafsX4 (L143AfsX4) at the protein level. The normal sequence, with the bases that are deleted in braces, is gGTC{AT}TGCT, where the capital letters are exonic and lowercase letter is intronic. The deletion causes a frameshift, which changes a Leucine to an Alanine at codon 143, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.426_427delAT has been observed in association with classic or attenuated Familial Adenomatous Polyposis and has been described as an American founder pathogenic variant (Spirio 1993, Friedl 2005, Neklason 2008). Based on the currently available evidence, we consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2022	The c.426_427delAT pathogenic mutation, located in coding exon 4 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 426 to 427, causing a translational frameshift with a predicted alternate stop codon (p.L143Afs*4). This mutation has been reported in families with attenuated familial adenomatous polyposis (AFAP) and in a family with AFAP and pilomatrixomas (Castellsagué E et al. Gastroenterology 2010 Aug;139(2):439-47, 447.e1; Trufant J et al. J. Cutan. Pathol. 2012 Apr;39(4):440-3). This alteration has been proposed to be an American founder mutation for AFAP (Neklason et al. Clin. Gastroenterol. Hepatol. 2008 Jan;6(1):46-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	This variant deletes 2 nucleotides in exon 5 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial adenomatous polyposis and attenuated familial adenomatous polyposis (PMID: 8252630, 8625067, 18063416, 18063416, 20434453, 22150579, 22809634, 23159591). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 01, 2018

Variant summary: APC c.426_427delAT (p.Leu143AlafsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 119962 control chromosomes. c.426_427delAT has been reported in the literature as an American founder mutation in several large kindreds with Familial Adenomatous Polyposis. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 08, 2017

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Leu143Alafs*4 variant was identified in the literature in 10 of 2606 chromosomes (frequency 0.004) from individuals with familial adenomatous polyposis (Castellsague 2010, Friedl 2005, Spirio 1993, Trufant 2012). This variant was also identified in the HGMD and InSIGHT Colon Cancer databases. It has been shown to segregate with disease (Nekalson 2008 18063416, Spirio 1993), has and is associated with an attenuated APC phenotype (Castellsague 2010, Nekalson 2008, Trufant 2012). The p.Leu143Alafs*4 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 143 and leads to a premature stop codon 3 codons downstream. This alteration would typically be predicted to result in a truncated or absent protein and loss of function; however, two studies have demonstrated that for APC mutations closer to the 5’ terminus, an internal ribosome entry site is utilized to initiate translation at codon 184, resulting in a partially functional N-terminally truncated protein, which results in an attenuated phenotype (Heppner Goss 2002, Trufant 2012). In summary, based on the above information, this variant is classified as pathogenic. -

Classic or attenuated familial adenomatous polyposis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 23, 2023

This variant deletes 2 nucleotides in exon 5 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least nine individuals affected with FAP/AFAP (PMID: 18063416, 15300576, 20223039, 26681312, 22809634, 22150579, 20434453, 8625067). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782557; hg19: chr5-112111328; COSMIC: COSV57332002; COSMIC: COSV57332002;