NM_000038.6(APC):c.221-1G>A AND Familial adenomatous polyposis 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 4, 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:: RCV003335203.3

Allele description [Variation Report for NM_000038.6(APC):c.221-1G>A]

NM_000038.6(APC):c.221-1G>A

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.221-1G>A

HGVS:

NC_000005.10:g.112767188G>A
NG_008481.4:g.79668G>A
NM_000038.6:c.221-1G>AMANE SELECT
NM_001127510.3:c.221-1G>A
NM_001127511.3:c.251-1G>A
NM_001354895.2:c.221-1G>A
NM_001354896.2:c.221-1G>A
NM_001354897.2:c.251-1G>A
NM_001354898.2:c.146-1G>A
NM_001354899.2:c.221-1G>A
NM_001354900.2:c.44-1G>A
NM_001354901.2:c.44-1G>A
NM_001354902.2:c.251-1G>A
NM_001354903.2:c.221-1G>A
NM_001354904.2:c.146-1G>A
NM_001354905.2:c.44-1G>A
NM_001354906.2:c.-815-1G>A
NM_001407446.1:c.251-1G>A
NM_001407447.1:c.221-1G>A
NM_001407448.1:c.221-1G>A
NM_001407449.1:c.221-1G>A
NM_001407450.1:c.221-1G>A
NM_001407451.1:c.146-1G>A
NM_001407452.1:c.221-1G>A
NM_001407453.1:c.44-1G>A
NM_001407454.1:c.221-1G>A
NM_001407455.1:c.221-1G>A
NM_001407456.1:c.221-1G>A
NM_001407457.1:c.221-1G>A
NM_001407458.1:c.221-1G>A
NM_001407459.1:c.221-1G>A
NM_001407460.1:c.221-1G>A
NM_001407467.1:c.221-1G>A
NM_001407469.1:c.221-1G>A
NM_001407470.1:c.-815-1G>A
NM_001407471.1:c.-815-1G>A
NM_001407472.1:c.-815-1G>A
LRG_130:g.79668G>A
NC_000005.9:g.112102885G>A
NM_000038.5:c.221-1G>A

Links:

dbSNP: rs863225327

NCBI 1000 Genomes Browser:

rs863225327

Molecular consequence:

NM_000038.6:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001127510.3:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001127511.3:c.251-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354895.2:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354896.2:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354897.2:c.251-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354898.2:c.146-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354899.2:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354900.2:c.44-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354901.2:c.44-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354902.2:c.251-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354903.2:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354904.2:c.146-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354905.2:c.44-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354906.2:c.-815-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407446.1:c.251-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407447.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407448.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407449.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407450.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407451.1:c.146-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407452.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407453.1:c.44-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407454.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407455.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407456.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407457.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407458.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407459.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407460.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407467.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407469.1:c.221-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407470.1:c.-815-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407471.1:c.-815-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407472.1:c.-815-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001409909	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20682701, 28492532
SCV004045660	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Apr 25, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001409909

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 4, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004045660

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(Apr 25, 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

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

Woods MO, Younghusband HB, Parfrey PS, Gallinger S, McLaughlin J, Dicks E, Stuckless S, Pollett A, Bapat B, Mrkonjic M, de la Chapelle A, Clendenning M, Thibodeau SN, Simms M, Dohey A, Williams P, Robb D, Searle C, Green JS, Green RC.

Gut. 2010 Oct;59(10):1369-77. doi: 10.1136/gut.2010.208462. Epub 2010 Aug 3.

PubMed [citation]

PMID:: 20682701
PMCID:: PMC3047452

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 Invitae, SCV001409909.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 217947). Disruption of this splice site has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 20682701). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

#	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., SCV004045660.2

#	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 likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

#	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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