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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 18, 2019
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:: RCV000499742.12

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 multiple polyposis syndrome (FAP)
Synonyms:: Familial adenomatous polyposis of the colon; Familial polyposis of the colon; Familial intestinal polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0021055; MedGen: C0032580; OMIM: PS175100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000781068	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001361364	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 18, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20223039, 24841357, 20924072 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000781068

Center for Human Genetics, Inc, Center for Human Genetics, Inc

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 1, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001361364

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 18, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients.

Friedl W, Aretz S.

Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. doi: 10.1186/1897-4287-3-3-95.

PubMed [citation]

PMID:: 20223039
PMCID:: PMC2837297

See all PubMed Citations (4)

Details of each submission

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781068.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361364.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: APC c.904C>T (p.Arg302X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1690C>T, p.Arg564X; c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; c.3340C>T, p.Arg1114X). The variant was absent in 251112 control chromosomes (gnomAD). The variant, c.904C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Friedl_2005, Rivera_2010, Lin_2014). 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Oct 13, 2024

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