rs587781694

Positions:

• chr5-112766334-TAAAC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000038.6(APC):​c.147_150del​(p.Lys49AsnfsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,450,662 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. K49K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.09

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-112766334-TAAAC-T is Pathogenic according to our data. Variant chr5-112766334-TAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 141368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112766334-TAAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.147_150del	p.Lys49AsnfsTer20	frameshift_variant	3/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.147_150del	p.Lys49AsnfsTer20	frameshift_variant	3/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1450662 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 722576

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: 0.00000635

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Oncology Laboratory, Hospital Clínico San Carlos	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Lys49Asnfs*20) 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 colon polyps, attenuated adenomatous polyposis (AFAP) and familial adenomatous polyposis (FAP) (PMID: 19531215, 20924072, 26681312). ClinVar contains an entry for this variant (Variation ID: 141368). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 23, 2021	This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals with colon polyps, attenuated adenomatous polyposis (AFAP) and familial adenomatous polyposis (FAP) in the published literature (PMID: 19531215 (2009), 20924072 (2011), 23159591 (2013), 26681312 (2015), 31285513 (2019)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 19531215, 20924072); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 19531215, 20924072, 31285513) -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 20, 2021

Variant summary: APC c.147_150delACAA (p.Lys49AsnfsX20) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251042 control chromosomes (gnomAD). c.147_150delACAA has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Gomez-Fernandez_2009, Rivera_2011, Lorca_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Lys49AsnfsX20 variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families with FAP (Gomez-Fernandez 2009, Rivera 2011). The variant was also identified in HGMD, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as a pathogenic variant by the Ambry Genetics), GeneInsight VariantWire database (1X, classified as “pathogenic” by a clinical laboratory), and UMD (12X).The p.Lys49AsnfsX20 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 49 and leads to a premature stop codon 20 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. This alteration would typically be predicted to result in a truncated or absent protein and loss of function; however, one study has 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). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Classic or attenuated familial adenomatous polyposis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 08, 2024

The c.147_150del (p.Lys49Asnfs*20) variant in the APC gene is located on the exon 3 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Lys49Asnfs*20), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis and attenuated adenomatous polyposis (PMID: 20924072, 31285513, 19531215, 26681312). Alterations that result in premature termination in the N-terminus of the APC protein are associated with an attenuated phenotype and may have incomplete penetrance compared to classic familial adenomatous polyposis syndrome (PMID: 9585611, 11257105). Loss-of-function variants of APC are known to be pathogenic (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar as pathogenic (ID: 141368). The variant is absent in the general population database (gnomAD). Therefore, the c.147_150del (p.Lys49Asnfs*20) variant of APC has been classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.147_150delACAA pathogenic mutation, located in coding exon 2 of the APC gene, results from a deletion of 4 nucleotides between positions 147 and 150, causing a translational frameshift with a predicted alternate stop codon (p.K49Nfs*20). This mutation has been reported in multiple individuals with features of both familial adenomatous polyposis (FAP) and attenuated FAP (Gomez-Fernandez N et al. BMC Med. Genet. 2009 Jun 16;10:57; Rivera B et al. Ann. Oncol. 2011 Apr;22(4):903-9; Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). 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. However, alterations that result in premature termination in coding exon 2 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised. -

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: rs587781694; hg19: chr5-112102031;