NM_000038.6(APC):c.5952_5955del (p.Glu1985fs) AND Familial adenomatous polyposis 1

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 12, 2016
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:: RCV000411671.1

Allele description

NM_000038.6(APC):c.5952_5955del (p.Glu1985fs)

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.5952_5955del (p.Glu1985fs)

HGVS:

NC_000005.10:g.112841546_112841549del
NG_008481.4:g.154026_154029del
NM_000038.6:c.5952_5955del
NM_001127510.3:c.5952_5955del
NM_001127511.3:c.5898_5901del
NM_001354895.2:c.5952_5955del
NM_001354896.2:c.6006_6009del
NM_001354897.2:c.5982_5985del
NM_001354898.2:c.5877_5880del
NM_001354899.2:c.5868_5871del
NM_001354900.2:c.5829_5832del
NM_001354901.2:c.5775_5778del
NM_001354902.2:c.5679_5682del
NM_001354903.2:c.5649_5652del
NM_001354904.2:c.5574_5577del
NM_001354905.2:c.5472_5475del
NM_001354906.2:c.5103_5106del
NP_000029.2:p.Glu1985fs
NP_001120982.1:p.Glu1985fs
NP_001120983.2:p.Glu1967fs
NP_001341824.1:p.Glu1985fs
NP_001341825.1:p.Glu2003fs
NP_001341826.1:p.Glu1995fs
NP_001341827.1:p.Glu1960fs
NP_001341828.1:p.Glu1957fs
NP_001341829.1:p.Glu1944fs
NP_001341830.1:p.Glu1926fs
NP_001341831.1:p.Glu1894fs
NP_001341832.1:p.Glu1884fs
NP_001341833.1:p.Glu1859fs
NP_001341834.1:p.Glu1825fs
NP_001341835.1:p.Glu1702fs
LRG_130:g.154026_154029del
NC_000005.9:g.112177243_112177246del
NM_000038.5:c.5952_5955delTGAA

Protein change:

E1702fs

Links:

dbSNP: rs1057517544

NCBI 1000 Genomes Browser:

rs1057517544

Molecular consequence:

NM_000038.6:c.5952_5955del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127510.3:c.5952_5955del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127511.3:c.5898_5901del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354895.2:c.5952_5955del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354896.2:c.6006_6009del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354897.2:c.5982_5985del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354898.2:c.5877_5880del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354899.2:c.5868_5871del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354900.2:c.5829_5832del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354901.2:c.5775_5778del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354902.2:c.5679_5682del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354903.2:c.5649_5652del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354904.2:c.5574_5577del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354905.2:c.5472_5475del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354906.2:c.5103_5106del - 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:: MedGen: C2713442; OMIM: 175100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488117	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Dec 30, 2015)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000552661	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 12, 2016)	germline	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

SCV000488117

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Likely pathogenic
(Dec 30, 2015)

unknown

clinical testing

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

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV000552661

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 12, 2016)

germline

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

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

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Counsyl, SCV000488117.1

#	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

From Invitae, SCV000552661.2

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

Description

This sequence change deletes 4 nucleotides from exon 16 of the APC mRNA (c.5952_5955delTGAA), causing a frameshift at codon 1985. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Glu1985Leufs*58). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated APC protein. Loss-of-function variants in APC are known to be pathogenic. This particular variant has been reported in the literature in an individual suspected of familial adenomatous polyposis (FAP) (PMID: 20223039). This variant removes the Basic Domain, the EB1 Binding Site, and the HDLG Binding Site of the APC protein, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect of this variant on APC protein function, a different truncating variant, c.7932_7935del (p.Tyr2645Lysfs*14), that only removes the EB1 and HDLG binding sites has been reported in several individuals with familial adenomatous polyposis (FAP) and attenuated FAP (PMID: 1316610, 8381579, 9824584, 22135120). These observations suggest that the C-terminal portion of the protein is clinically important. For these reasons, this variant has been classified as Likely 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: Mar 26, 2020

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