5-112821953-C-G

Variant names:

• chr5-112821953-C-G
• rs1060503333
• NM_000038.6:c.1370C>G

Variant summary

Our verdict is Pathogenic. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S457S) has been classified as Likely benign. 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: 7.91
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 411488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1370C>G	p.Ser457*	stop_gained	Exon 11 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1370C>G	p.Ser457*	stop_gained	Exon 11 of 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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.1370C>G (p.Ser457*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in individuals and families with familial adenomatous polyposis (FAP) (PMIDs: 34224960 (2021), 17411426 (2007), 20223039 (2005)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Jul 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 07, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Familial adenomatous polyposis 1 Pathogenic:2

May 01, 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.

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). ClinVar contains an entry for this variant (Variation ID: 411488). For these reasons, this variant has been classified as Pathogenic.

not specified Pathogenic:1

Sep 05, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classic or attenuated familial adenomatous polyposis Pathogenic:1

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 13, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.0	.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.65
LIST_S2	Benign	0.0	.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.
PhyloP100		7.9
PROVEAN	Benign	0.0	.;.;.;.;.
Sift	Pathogenic	0.0	.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.
Vest4		0.0
GERP RS		5.2
PromoterAI		0.021	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060503333; hg19: chr5-112157650;