NM_000038.6(APC):c.7678C>T (p.Arg2560Ter) AND Familial adenomatous polyposis 1

delete

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 16, 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:: RCV003336208.3

Allele description

NM_000038.6(APC):c.7678C>T (p.Arg2560Ter)

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.7678C>T (p.Arg2560Ter)

HGVS:

NC_000005.10:g.112843272C>T
NG_008481.4:g.155752C>T
NM_000038.6:c.7678C>TMANE SELECT
NM_001127510.3:c.7678C>T
NM_001127511.3:c.7624C>T
NM_001354895.2:c.7678C>T
NM_001354896.2:c.7732C>T
NM_001354897.2:c.7708C>T
NM_001354898.2:c.7603C>T
NM_001354899.2:c.7594C>T
NM_001354900.2:c.7555C>T
NM_001354901.2:c.7501C>T
NM_001354902.2:c.7405C>T
NM_001354903.2:c.7375C>T
NM_001354904.2:c.7300C>T
NM_001354905.2:c.7198C>T
NM_001354906.2:c.6829C>T
NP_000029.2:p.Arg2560Ter
NP_001120982.1:p.Arg2560Ter
NP_001120983.2:p.Arg2542Ter
NP_001341824.1:p.Arg2560Ter
NP_001341825.1:p.Arg2578Ter
NP_001341826.1:p.Arg2570Ter
NP_001341827.1:p.Arg2535Ter
NP_001341828.1:p.Arg2532Ter
NP_001341829.1:p.Arg2519Ter
NP_001341830.1:p.Arg2501Ter
NP_001341831.1:p.Arg2469Ter
NP_001341832.1:p.Arg2459Ter
NP_001341833.1:p.Arg2434Ter
NP_001341834.1:p.Arg2400Ter
NP_001341835.1:p.Arg2277Ter
LRG_130:g.155752C>T
NC_000005.9:g.112178969C>T
NM_000038.5:c.7678C>T

Protein change:

R2277*

Links:

dbSNP: rs1580685528

NCBI 1000 Genomes Browser:

rs1580685528

Molecular consequence:

NM_000038.6:c.7678C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001127510.3:c.7678C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001127511.3:c.7624C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354895.2:c.7678C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354896.2:c.7732C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354897.2:c.7708C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354898.2:c.7603C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354899.2:c.7594C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354900.2:c.7555C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354901.2:c.7501C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354902.2:c.7405C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354903.2:c.7375C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354904.2:c.7300C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354905.2:c.7198C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354906.2:c.6829C>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
SCV000950664	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 21, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9824584, 1316610, 27081525, 8381579, 22135120, 15311282, 17293347, 28492532
SCV004045630	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (May 16, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000950664

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 21, 2022)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004045630

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(May 16, 2023)

unknown

clinical testing

Citation Link

Help

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.

Brensinger JD, Laken SJ, Luce MC, Powell SM, Vance GH, Ahnen DJ, Petersen GM, Hamilton SR, Giardiello FM.

Gut. 1998 Oct;43(4):548-52.

PubMed [citation]

PMID:: 9824584
PMCID:: PMC1727294

Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients.

Miyoshi Y, Ando H, Nagase H, Nishisho I, Horii A, Miki Y, Mori T, Utsunomiya J, Baba S, Petersen G, et al.

Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6.

PubMed [citation]

PMID:: 1316610
PMCID:: PMC49100

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000950664.4

#	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.Arg2560*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 284 amino acid(s) of the APC protein. For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. ClinVar contains an entry for this variant (Variation ID: 654491). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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 Myriad Genetics, Inc., SCV004045630.2

#	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

Last Updated: Jun 2, 2024

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