NM_000038.6(APC):c.904C>T (p.Arg302Ter) AND Familial adenomatous polyposis 1

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Oct 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000000834.25

Allele description [Variation Report for NM_000038.6(APC):c.904C>T (p.Arg302Ter)]

NM_000038.6(APC):c.904C>T (p.Arg302Ter)

Gene:

APC:APC regulator of WNT signaling pathway [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q22.2

Genomic location:

Preferred name:

NM_000038.6(APC):c.904C>T (p.Arg302Ter)

HGVS:

NC_000005.10:g.112815564C>T
NG_008481.4:g.128044C>T
NM_000038.6:c.904C>TMANE SELECT
NM_001127510.3:c.904C>T
NM_001127511.3:c.850C>T
NM_001354895.2:c.904C>T
NM_001354896.2:c.904C>T
NM_001354897.2:c.934C>T
NM_001354898.2:c.829C>T
NM_001354899.2:c.820C>T
NM_001354900.2:c.727C>T
NM_001354901.2:c.727C>T
NM_001354902.2:c.934C>T
NM_001354903.2:c.904C>T
NM_001354904.2:c.829C>T
NM_001354905.2:c.727C>T
NM_001354906.2:c.55C>T
NP_000029.2:p.Arg302Ter
NP_001120982.1:p.Arg302Ter
NP_001120983.2:p.Arg284Ter
NP_001341824.1:p.Arg302Ter
NP_001341825.1:p.Arg302Ter
NP_001341826.1:p.Arg312Ter
NP_001341827.1:p.Arg277Ter
NP_001341828.1:p.Arg274Ter
NP_001341829.1:p.Arg243Ter
NP_001341830.1:p.Arg243Ter
NP_001341831.1:p.Arg312Ter
NP_001341832.1:p.Arg302Ter
NP_001341833.1:p.Arg277Ter
NP_001341834.1:p.Arg243Ter
NP_001341835.1:p.Arg19Ter
LRG_130:g.128044C>T
NC_000005.9:g.112151261C>T
NM_000038.5:c.904C>T
NP_000029.2:p.Arg302*
p.R302*

Protein change:

R19*; ARG302TER

Links:

OMIM: 611731.0002; OMIM: 611731.0006; dbSNP: rs137854568

NCBI 1000 Genomes Browser:

rs137854568

Molecular consequence:

NM_000038.6:c.904C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001127510.3:c.904C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001127511.3:c.850C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354895.2:c.904C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354896.2:c.904C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354897.2:c.934C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354898.2:c.829C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354899.2:c.820C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354900.2:c.727C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354901.2:c.727C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354902.2:c.934C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354903.2:c.904C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354904.2:c.829C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354905.2:c.727C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354906.2:c.55C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Familial adenomatous polyposis 1 (FAP1)
Synonyms:: POLYPOSIS, ADENOMATOUS INTESTINAL; FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED; APC-Associated Polyposis Conditions
Identifiers:: MONDO: MONDO:0021056; MedGen: C2713442; OMIM: 175100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020980	OMIM	no assertion criteria provided	Pathogenic (Aug 9, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000282851	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17963004, 1651563, 11317365, 16317745, 20685668, 23159591, 23561487, 28492532
SCV000536922	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Pathogenic (Jun 11, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000838072	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004044642	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 27, 2023)	unknown	clinical testing	Citation Link,
SCV004207250	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Identification and characterization of the familial adenomatous polyposis coli gene.

Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, et al.

Cell. 1991 Aug 9;66(3):589-600.

PubMed [citation]

PMID:: 1651174

Mutational screening of the APC gene in Chilean families with familial adenomatous polyposis: nine novel truncating mutations.

De la Fuente MK, Alvarez KP, Letelier AJ, Bellolio F, Acuña ML, León FS, Pinto E, Carvallo P, López-Köstner F.

Dis Colon Rectum. 2007 Dec;50(12):2142-8.

PubMed [citation]

PMID:: 17963004

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000020980.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with familial adenomatous polyposis-1 (175100), Groden et al. (1991) identified a heterozygous 904C-T transition in exon 8 of the APC gene, resulting in an arg-to-ter substitution.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000282851.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Arg302*) 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, Gardner syndrome, and colorectal cancer (PMID: 1651563, 11317365, 16317745, 20685668, 23159591, 23561487). ClinVar contains an entry for this variant (Variation ID: 798). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536922.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000838072.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004044642.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004207250.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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