NM_000038.6(APC):c.4420G>A (p.Ala1474Thr) AND Familial adenomatous polyposis 1

Germline classification:: Benign (4 submissions)
Last evaluated:: Feb 26, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000987573.17

Allele description [Variation Report for NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)]

NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)

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.4420G>A (p.Ala1474Thr)

Other names:

p.A1474T:GCT>ACT; NM_000038.6(APC):c.4420G>A

HGVS:

NC_000005.10:g.112840014G>A
NG_008481.4:g.152494G>A
NM_000038.6:c.4420G>AMANE SELECT
NM_001127510.3:c.4420G>A
NM_001127511.3:c.4366G>A
NM_001354895.2:c.4420G>A
NM_001354896.2:c.4474G>A
NM_001354897.2:c.4450G>A
NM_001354898.2:c.4345G>A
NM_001354899.2:c.4336G>A
NM_001354900.2:c.4297G>A
NM_001354901.2:c.4243G>A
NM_001354902.2:c.4147G>A
NM_001354903.2:c.4117G>A
NM_001354904.2:c.4042G>A
NM_001354905.2:c.3940G>A
NM_001354906.2:c.3571G>A
NP_000029.2:p.Ala1474Thr
NP_001120982.1:p.Ala1474Thr
NP_001120983.2:p.Ala1456Thr
NP_001341824.1:p.Ala1474Thr
NP_001341825.1:p.Ala1492Thr
NP_001341826.1:p.Ala1484Thr
NP_001341827.1:p.Ala1449Thr
NP_001341828.1:p.Ala1446Thr
NP_001341829.1:p.Ala1433Thr
NP_001341830.1:p.Ala1415Thr
NP_001341831.1:p.Ala1383Thr
NP_001341832.1:p.Ala1373Thr
NP_001341833.1:p.Ala1348Thr
NP_001341834.1:p.Ala1314Thr
NP_001341835.1:p.Ala1191Thr
LRG_130t1:c.4420G>A
LRG_130:g.152494G>A
NC_000005.9:g.112175711G>A
NM_000038.4:c.4420G>A
NM_000038.5:c.4420G>A
NM_001127510.2:c.4420G>A
p.A1474T

Protein change:

A1191T

Links:

dbSNP: rs139387758

NCBI 1000 Genomes Browser:

rs139387758

Molecular consequence:

NM_000038.6:c.4420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127510.3:c.4420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127511.3:c.4366G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354895.2:c.4420G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354896.2:c.4474G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354897.2:c.4450G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354898.2:c.4345G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354899.2:c.4336G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354900.2:c.4297G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354901.2:c.4243G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354902.2:c.4147G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354903.2:c.4117G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354904.2:c.4042G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354905.2:c.3940G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354906.2:c.3571G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000252587	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001136913	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV003836603	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)	Benign (Feb 26, 2023)	germline	curation	Citation Link,
SCV005084458	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Benign (Apr 10, 2024)	unknown	clinical testing	Citation Link

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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, curation
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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000252587.12

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001136913.1

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

#	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 ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel, SCV003836603.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID: 18199528). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).

#	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., SCV005084458.1

#	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 benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

#	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: Nov 24, 2024

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