NM_000038.6(APC):c.475dup (p.Tyr159fs) AND Familial adenomatous polyposis 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 10, 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:: RCV003337248.2

Allele description [Variation Report for NM_000038.6(APC):c.475dup (p.Tyr159fs)]

NM_000038.6(APC):c.475dup (p.Tyr159fs)

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.475dup (p.Tyr159fs)

HGVS:

NC_000005.10:g.112775681dup
NG_008481.4:g.88161dup
NM_000038.6:c.475dupMANE SELECT
NM_001127510.3:c.475dup
NM_001127511.3:c.505dup
NM_001354895.2:c.475dup
NM_001354896.2:c.475dup
NM_001354897.2:c.505dup
NM_001354898.2:c.400dup
NM_001354899.2:c.475dup
NM_001354900.2:c.298dup
NM_001354901.2:c.298dup
NM_001354902.2:c.505dup
NM_001354903.2:c.475dup
NM_001354904.2:c.400dup
NM_001354905.2:c.298dup
NM_001354906.2:c.-561dup
NP_000029.2:p.Tyr159fs
NP_001120982.1:p.Tyr159fs
NP_001120983.2:p.Tyr169fs
NP_001341824.1:p.Tyr159fs
NP_001341825.1:p.Tyr159fs
NP_001341826.1:p.Tyr169fs
NP_001341827.1:p.Tyr134fs
NP_001341828.1:p.Tyr159fs
NP_001341829.1:p.Tyr100fs
NP_001341830.1:p.Tyr100fs
NP_001341831.1:p.Tyr169fs
NP_001341832.1:p.Tyr159fs
NP_001341833.1:p.Tyr134fs
NP_001341834.1:p.Tyr100fs
LRG_130:g.88161dup
NC_000005.9:g.112111376_112111377insT
NC_000005.9:g.112111378dup
NM_000038.5:c.475dup
NM_000038.5:c.475dupT

Protein change:

Y100fs

Links:

dbSNP: rs863225361

NCBI 1000 Genomes Browser:

rs863225361

Molecular consequence:

NM_001354906.2:c.-561dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000038.6:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127510.3:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127511.3:c.505dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354895.2:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354896.2:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354897.2:c.505dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354898.2:c.400dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354899.2:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354900.2:c.298dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354901.2:c.298dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354902.2:c.505dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354903.2:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354904.2:c.400dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354905.2:c.298dup - 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
SCV000822589	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17963004, 20685668, 28492532
SCV004044881	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 26, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000822589

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 10, 2023)

germline

clinical testing

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

SCV004044881

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Apr 26, 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	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

Mutational screening of the APC gene in Chilean families with familial adenomatous polyposis: nine novel truncating mutations.

De la Fuente MK, Alvarez KP, Letelier AJ, Bellolio F, Acuña ML, León FS, Pinto E, Carvallo P, López-Köstner F.

Dis Colon Rectum. 2007 Dec;50(12):2142-8.

PubMed [citation]

PMID:: 17963004

Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP.

Lagarde A, Rouleau E, Ferrari A, Noguchi T, Qiu J, Briaux A, Bourdon V, Rémy V, Gaildrat P, Adélaïde J, Birnbaum D, Lidereau R, Sobol H, Olschwang S.

J Med Genet. 2010 Oct;47(10):721-2. doi: 10.1136/jmg.2010.078964. Epub 2010 Aug 3.

PubMed [citation]

PMID:: 20685668

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000822589.7

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

Description

This sequence change creates a premature translational stop signal (p.Tyr159Leufs*9) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 217990). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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., SCV004044881.2

#	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: May 1, 2024

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