NM_000038.6(APC):c.4612_4613del (p.Glu1538fs) AND Familial adenomatous polyposis 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 13, 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:: RCV002512626.13

Allele description [Variation Report for NM_000038.6(APC):c.4612_4613del (p.Glu1538fs)]

NM_000038.6(APC):c.4612_4613del (p.Glu1538fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

5q22.2

Genomic location:

Preferred name:

NM_000038.6(APC):c.4612_4613del (p.Glu1538fs)

HGVS:

NC_000005.10:g.112840206_112840207del
NG_008481.4:g.152685_152686del
NG_008481.4:g.152686_152687del
NM_000038.6:c.4612_4613delMANE SELECT
NM_001127510.3:c.4612_4613del
NM_001127511.3:c.4558_4559del
NM_001354895.2:c.4612_4613del
NM_001354896.2:c.4666_4667del
NM_001354897.2:c.4642_4643del
NM_001354898.2:c.4537_4538del
NM_001354899.2:c.4528_4529del
NM_001354900.2:c.4489_4490del
NM_001354901.2:c.4435_4436del
NM_001354902.2:c.4339_4340del
NM_001354903.2:c.4309_4310del
NM_001354904.2:c.4234_4235del
NM_001354905.2:c.4132_4133del
NM_001354906.2:c.3763_3764del
NP_000029.2:p.Glu1538fs
NP_001120982.1:p.Glu1538fs
NP_001120983.2:p.Glu1520fs
NP_001341824.1:p.Glu1538fs
NP_001341825.1:p.Glu1556fs
NP_001341826.1:p.Glu1548fs
NP_001341827.1:p.Glu1513fs
NP_001341828.1:p.Glu1510fs
NP_001341829.1:p.Glu1497fs
NP_001341830.1:p.Glu1479fs
NP_001341831.1:p.Glu1447fs
NP_001341832.1:p.Glu1437fs
NP_001341833.1:p.Glu1412fs
NP_001341834.1:p.Glu1378fs
NP_001341835.1:p.Glu1255fs
LRG_130:g.152686_152687del
NC_000005.10:g.112840206_112840207delGA
NC_000005.9:g.112175902_112175903del
NC_000005.9:g.112175903_112175904del
NG_008481.4:g.152685_152686del
NM_000038.5:c.4612_4613delGA

Protein change:

E1255fs

Links:

OMIM: 611731.0030; dbSNP: rs387906236

NCBI 1000 Genomes Browser:

rs387906236

Molecular consequence:

NM_000038.6:c.4612_4613del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127510.3:c.4612_4613del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127511.3:c.4558_4559del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354895.2:c.4612_4613del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354896.2:c.4666_4667del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354897.2:c.4642_4643del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354898.2:c.4537_4538del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354899.2:c.4528_4529del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354900.2:c.4489_4490del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354901.2:c.4435_4436del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354902.2:c.4339_4340del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354903.2:c.4309_4310del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354904.2:c.4234_4235del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354905.2:c.4132_4133del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354906.2:c.3763_3764del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000768087	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 8162051, 8594558, 20223039, 20513532, 20685668, 21643010, 21779980, 22987206, 15311282, 17293347, 9824584, 1316610, 27081525, 8381579, 22135120, 28492532
SCV004044003	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (May 11, 2023)	unknown	clinical testing	Citation Link,
SCV004200474	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000768087

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 13, 2023)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

SCV004044003

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(May 11, 2023)

unknown

clinical testing

Citation Link,

SCV004200474

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 28, 2023)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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

Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.

Gayther SA, Wells D, SenGupta SB, Chapman P, Neale K, Tsioupra K, Delhanty JD.

Hum Mol Genet. 1994 Jan;3(1):53-6.

PubMed [citation]

PMID:: 8162051

APC gene: database of germline and somatic mutations in human tumors and cell lines.

Béroud C, Soussi T.

Nucleic Acids Res. 1996 Jan 1;24(1):121-4.

PubMed [citation]

PMID:: 8594558
PMCID:: PMC145597

See all PubMed Citations (17)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000768087.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This sequence change creates a premature translational stop signal (p.Glu1538Ilefs*5) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1306 amino acid(s) of the APC protein. 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 (PMID: 8162051, 8594558, 20223039, 20513532, 20685668, 21643010, 21779980, 22987206). ClinVar contains an entry for this variant (Variation ID: 823). 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. 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. 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 Myriad Genetics, Inc., SCV004044003.2

#	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 frameshift 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, SCV004200474.2

#	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: Nov 10, 2024

ClinVar

Relating variation to medicine