chr5-112821953-C-G

Position:

• chr5-112821953-C-G

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.1370C>G​(p.Ser457*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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:7
• Conservation: PhyloP100: 7.91

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 (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 5-112821953-C-G is Pathogenic according to our data. Variant chr5-112821953-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 411488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112821953-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1370C>G	p.Ser457*	stop_gained	11/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1370C>G	p.Ser457*	stop_gained	11/16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 01, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 411488). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 17411426, 20223039, 20685668). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser457*) 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2017	This pathogenic variant is denoted APC c.1370C>G at the cDNA level and p.Ser457Ter (S457X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Ser457Ter has been observed in multiple individuals with Familial Adenomatous Polyposis (FAP) or Attenuated FAP, including at least two related individuals with congenital hypertrophy of the retinal pigment epithelium (CHRPE) (Wallis 1994, Michils 2002, Friedl 2005, Stekrova 2007). Based on currently available evidence, we consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 05, 2016

- -

Classic or attenuated familial adenomatous polyposis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 28, 2024

The c.1370C>G (p.Ser457*) variant in the APC gene is located on the exon 11 and introduces a premature translation termination codon (p.Ser457*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 31062380, 20223039, 22135120, 31802619, 17411426). Loss-of-function variants of APC are known to be pathogenic (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar (ID: 411488). The variant is absent in the general population database (gnomAD). Therefore, the c.1370C>G (p.Ser457*) variant of APC has been classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The p.S457* pathogenic mutation (also known as c.1370C>G), located in coding exon 10 of the APC gene, results from a C to G substitution at nucleotide position 1370. This changes the amino acid from a serine to a stop codon within coding exon 10. This mutation has been identified in multiple individuals/families with familial adenomatous polyposis or attenuated familial adenomatous polyposis (Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Stekrova J et al. BMC Med. Genet. 2007;8:16; Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.98, 0.98
GERP RS		5.2

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: rs1060503333; hg19: chr5-112157650; COSMIC: COSV57377762;