NM_000038.6(APC):c.7692dup (p.Arg2565fs) AND Familial adenomatous polyposis 1

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:: RCV002530356.11

Allele description [Variation Report for NM_000038.6(APC):c.7692dup (p.Arg2565fs)]

NM_000038.6(APC):c.7692dup (p.Arg2565fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

5q22.2

Genomic location:

Preferred name:

NM_000038.6(APC):c.7692dup (p.Arg2565fs)

HGVS:

NC_000005.10:g.112843286dup
NG_008481.4:g.155766dup
NM_000038.6:c.7692dupMANE SELECT
NM_001127510.3:c.7692dup
NM_001127511.3:c.7638dup
NM_001354895.2:c.7692dup
NM_001354896.2:c.7746dup
NM_001354897.2:c.7722dup
NM_001354898.2:c.7617dup
NM_001354899.2:c.7608dup
NM_001354900.2:c.7569dup
NM_001354901.2:c.7515dup
NM_001354902.2:c.7419dup
NM_001354903.2:c.7389dup
NM_001354904.2:c.7314dup
NM_001354905.2:c.7212dup
NM_001354906.2:c.6843dup
NP_000029.2:p.Arg2565fs
NP_001120982.1:p.Arg2565fs
NP_001120983.2:p.Arg2547fs
NP_001341824.1:p.Arg2565fs
NP_001341825.1:p.Arg2583fs
NP_001341826.1:p.Arg2575fs
NP_001341827.1:p.Arg2540fs
NP_001341828.1:p.Arg2537fs
NP_001341829.1:p.Arg2524fs
NP_001341830.1:p.Arg2506fs
NP_001341831.1:p.Arg2474fs
NP_001341832.1:p.Arg2464fs
NP_001341833.1:p.Arg2439fs
NP_001341834.1:p.Arg2405fs
NP_001341835.1:p.Arg2282fs
LRG_130:g.155766dup
NC_000005.9:g.112178981_112178982insG
NC_000005.9:g.112178983dup
NM_000038.5:c.7692dupG

Protein change:

R2282fs

Links:

dbSNP: rs1554088600

NCBI 1000 Genomes Browser:

rs1554088600

Molecular consequence:

NM_000038.6:c.7692dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127510.3:c.7692dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127511.3:c.7638dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354895.2:c.7692dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354896.2:c.7746dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354897.2:c.7722dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354898.2:c.7617dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354899.2:c.7608dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354900.2:c.7569dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354901.2:c.7515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354902.2:c.7419dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354903.2:c.7389dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354904.2:c.7314dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354905.2:c.7212dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354906.2:c.6843dup - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000932880	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 30, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004045775	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

SCV000932880

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 30, 2020)

germline

clinical testing

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

SCV004045775

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000932880.4

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

Description

This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID:¬†487047). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Arg2565Glufs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 279 amino acids of the APC protein. 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. This variant disrupts the C-terminus of the APC protein. Other variant(s) that disrupt this region (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID:¬†9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that variants that disrupt this region of the protein are likely to be 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., SCV004045775.2

#	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

Last Updated: Sep 16, 2024

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