5-112828001-C-T

Variant names:

• chr5-112828001-C-T
• rs137854572
• NM_000038.6:c.1621C>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.1621C>T​(p.Gln541*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.84

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]

ENSG00000258864 (HGNC:):

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 5-112828001-C-T is Pathogenic according to our data. Variant chr5-112828001-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828001-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.1621C>T	p.Gln541*	stop_gained	Exon 13 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1621C>T	p.Gln541*	stop_gained	Exon 13 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.106C>T		non_coding_transcript_exon_variant	Exon 2 of 8	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

May 02, 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. -

Mar 30, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 30, 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.Gln541*) 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) (PMID: 1316610, 1324223, 11317365, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 806). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Oct 24, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted APC c.1621C>T at the cDNA level and p.Gln541Ter (Q541X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported several individuals with polyposis (Abraham 2000, De Rosa 2004, Fodde 1992, Friedl 2005, Miyoshi 1992, Resta 2001, Wallis 1999) and is considered pathogenic. -

Mar 06, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gln541X variant has been previously reported in the literature in at least 5 of 2936 proband chromsomes from individuals with familial adenomatous polyposis (Miyoshi 1992, Friedl 2005, Van der Luijt 2997, Fodde 1992, Wallis 1999). Furthermore, the variant was shown to segregate with disease in at least 4 affected family members increasing the likelihood this variant is pathogenic. This variant has also been reported in the HGMD, UMD, Cosmic, dbSNP (rs137854572), and LOVD databases. The p.Gln541X variant leads to a premature stop codon at position 541, which is predicted to lead to 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. In summary, based on the above information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 15, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q541* pathogenic mutation (also known as c.1621C>T), located in coding exon 12 of the APC gene, results from a C to T substitution at nucleotide position 1621. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been reported in multiple individuals of various ethnicities diagnosed with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc Natl Acad Sci U S A, 1992 May;89:4452-6; Fodde R et al. Genomics, 1992 Aug;13:1162-8; van der Luijt RB et al. Hum. Mutat., 1997;9:7-16; Wallis YL et al. J Med Genet, 1999 Jan;36:14-20; Resta N et al. Hum Mutat, 2001 May;17:434-5; De Rosa M et al. Hum Mutat, 2004 May;23:523-4; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Li N et al. J Gastroenterol Hepatol, 2019 Sep;34:1497-1503; Ambry internal data). 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. -

Brain tumor-polyposis syndrome 2 Pathogenic:1

Mar 30, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.98
GERP RS		4.5

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: rs137854572; hg19: chr5-112163698; COSMIC: COSV57345708;