5-112819026-C-T

Variant names:

• chr5-112819026-C-T
• rs775126020
• NM_000038.6:c.994C>T

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.994C>T​(p.Arg332*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,822 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 (★★). Variant results in nonsense mediated mRNA decay.

• 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:14 O:1
• Conservation: PhyloP100: 4.10

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 5-112819026-C-T is Pathogenic according to our data. Variant chr5-112819026-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 184937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112819026-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.994C>T	p.Arg332*	stop_gained	Exon 10 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.994C>T	p.Arg332*	stop_gained	Exon 10 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6 Other:1

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Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 APC-related phenotypes (PMID: 9585611, 10094557, 11748858, 20223039, 16461775, 25559809); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34326862, 28010732, 30072583, 16461775, 1646175, 11001924, 20223039, 20924072, 16134147, 17411426, 11748858, 19531215, 23159591, 25559809, 22987206, 11317365, 11960572, 19793053, 22425061, 20105204, 25525159, 9585611, 28790112, 29691710, 10094557, 31461190, 33468868, 33294277, 36225625, 33309985, 33664379) -

Dec 22, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with familial adenomatous polyposis (FAP) (PMIDs: 19531215 (2009), 11748858 (2001), 10713886 (2000)), suspected FAP (PMID: 20223039 (2005)), attenuated FAP (PMIDs: 17411426 (2007), 9585611 (1998)), colorectal cancer (PMID: 25559809 (2015)), and Lynch-like syndrome (PMID: 33294277 (2020)). Based on the available information, this variant is classified as pathogenic. -

May 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.994C>T; p.Arg332Ter variant (rs775126020) is reported in the literature in multiple individuals affected with familial adenomatous polyposis (FAP) and attenuated FAP (Aceto 2005, Cao 2000, Friedl 2005, Gomez-Fernandez 2009, Hutter 2001, Lamlum 2000, Rivera 2011, Sieber 2006, Soravia 1998, Stekrova 2007). This variant is reported in ClinVar (Variation ID: 184937), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. The vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Based on available information, this variant is considered to be pathogenic. References: Aceto G et al. Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. Hum Mutat. 2005 Oct;26(4):394. Cao X et al. APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients. Eur J Hum Genet. 2000 Jan;8(1):42-8. Friedl W and Aretz S. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Gomez-Fernandez N et al. Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations? BMC Med Genet. 2009 Jun 16;10:57. Hutter P et al. Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis. Hum Mutat. 2001 Dec;18(6):550. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Lamlum H et al. Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet. 2000 Sep 22;9(15):2215-21. Rivera B et al. Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study. Ann Oncol. 2011 Apr;22(4):903-9. Sieber OM et al. Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut. 2006 Oct;55(10):1440-8. Soravia C et al. Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet. 1998 Jun;62(6):1290-301. Stekrova J et al. Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. BMC Med Genet. 2007 Apr 5;8:16. -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 10-29-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Familial adenomatous polyposis 1 Pathogenic:3

Dec 18, 2024

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.Arg332*) 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 familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (PMID: 9585611, 11748858, 17411426, 19531215, 25559809). ClinVar contains an entry for this variant (Variation ID: 184937). For these reasons, this variant has been classified as Pathogenic. -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Apr 28, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 30, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R332* pathogenic mutation (also known as c.994C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been identified in many patients diagnosed with FAP or AFAP from various ethnicities (Soravia et al. Am J Hum Genet. 1998. 62:1290-1301; Gomez-Fernandez N et al. BMC Med Genet. 2009 Jun 16;10:57; Friedl W & Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Dec 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 of the APC gene, creating a 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 and families affected with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and colorectal cancer (PMID: 9585611, 10713886, 11001924, 11748858, 11317365, 16461775, 17411426, 19531215, 20223039, 23159591, 25590978). 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

Apr 18, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.994C>T (p.Arg332X) 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 276792 control chromosomes (gnomAD). The variant, c.994C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Cao_2000, Friedl_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach Pathogenic:1

Jan 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited polyposis and early onset colorectal cancer - germline testing Pathogenic:1

May 29, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PS4_Moderate,PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.98, 0.98
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs775126020; hg19: chr5-112154723; COSMIC: COSV57320525; COSMIC: COSV57320525;