NM_001127511.3(APC):c.-190G>A AND Familial adenomatous polyposis 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 9, 2024
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:: RCV000234994.18

Allele description [Variation Report for NM_001127511.3(APC):c.-190G>A]

NM_001127511.3(APC):c.-190G>A

Genes:

APC:APC regulator of WNT signaling pathway [Gene - OMIM - HGNC]
LOC129994371:ATAC-STARR-seq lymphoblastoid active region 22910 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

5q22.2

Genomic location:

Preferred name:

NM_001127511.3(APC):c.-190G>A

HGVS:

NC_000005.10:g.112707528G>A
NG_008481.4:g.20008G>A
NG_173817.1:g.151G>A
NM_001127511.3:c.-190G>A
NM_001354895.2:c.-373G>A
NM_001354897.2:c.-190G>A
NM_001354902.2:c.-190G>A
NM_001407446.1:c.-190G>A
NM_001407447.1:c.-373G>A
NM_001407448.1:c.-140G>A
NM_001407450.1:c.-140G>A
NM_001407452.1:c.-373G>A
NM_001407453.1:c.-164G>A
NM_001407456.1:c.-373G>A
NM_001407457.1:c.-140G>A
NM_001407458.1:c.-140G>A
NM_001407460.1:c.-373G>A
NM_001407469.1:c.-373G>A
NM_001407470.1:c.-1408G>A
NM_001407472.1:c.-1408G>A
LRG_130t3:c.-373G>A
LRG_130:g.20008G>A
NC_000005.9:g.112043225G>A
NM_000038.5:c.-30416G>A
NM_001127511.1:c.-373G>A
NM_001127511.2:c.-190G>A
NR_176365.1:n.31G>A
NR_176366.1:n.31G>A

Nucleotide change:

-190G-A

Links:

OMIM: 611731.0057; dbSNP: rs879253785

NCBI 1000 Genomes Browser:

rs879253785

Molecular consequence:

NM_001127511.3:c.-190G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354895.2:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354897.2:c.-190G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354902.2:c.-190G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407446.1:c.-190G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407447.1:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407448.1:c.-140G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407450.1:c.-140G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407452.1:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407453.1:c.-164G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407456.1:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407457.1:c.-140G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407458.1:c.-140G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407460.1:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407469.1:c.-373G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407470.1:c.-1408G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407472.1:c.-1408G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NR_176365.1:n.31G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176366.1:n.31G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000292339	OMIM	no assertion criteria provided	Pathogenic (Jul 12, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000647372	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27087319, 28492532
SCV001426488	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000292339

OMIM

no assertion criteria provided

Pathogenic
(Jul 12, 2016)

germline

literature only

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

SCV000647372

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 9, 2024)

germline

clinical testing

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

SCV001426488

Centogene AG - the Rare Disease Company

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Li J, Woods SL, Healey S, Beesley J, Chen X, Lee JS, Sivakumaran H, Wayte N, Nones K, Waterfall JJ, Pearson J, Patch AM, Senz J, Ferreira MA, Kaurah P, Mackenzie R, Heravi-Moussavi A, Hansford S, Lannagan TRM, Spurdle AB, Simpson PT, da Silva L, et al.

Am J Hum Genet. 2016 May 5;98(5):830-842. doi: 10.1016/j.ajhg.2016.03.001. Epub 2016 Apr 14.

PubMed [citation]

PMID:: 27087319
PMCID:: PMC4863475

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

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000292339.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 5 affected individuals over 3 generations of a family with profuse fundic gland polyps as well as colorectal polyposis (FAP1; 175100), Li et al. (2016) identified heterozygosity for a c.-190G-A transition (c.-190G-A, NM_001127511) in a YY1 binding motif in the APC promoter 1B. The mutation was not found in 2 unaffected family members. By EMSA, Li et al. (2016) demonstrated that the c.-190G-A mutation disrupts binding to the promoter 1B region in both AGS and RKO cells.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000647372.6

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

Description

This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of familial adenomatous polyposis (PMID: 27087319; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-190G>A. ClinVar contains an entry for this variant (Variation ID: 243008). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects APC function (PMID: 27087319). 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 Centogene AG - the Rare Disease Company, SCV001426488.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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