VCV000021030.58 - ClinVar

NM_000038.6(APC):c.5465T>A (p.Val1822Asp)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Benign

for Familial adenomatous polyposis 1

Classification is based on the expert panel submission

Feb 2023 by ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Vari…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.5465T>A (p.Val1822Asp)

Variation ID: 21030 Accession: VCV000021030.58

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112841059 (GRCh38) [ NCBI UCSC ] 5: 112176756 (GRCh37) [ NCBI UCSC ] 5: 112204655 (NCBI36) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Jan 24, 2026	Feb 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.5465T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Val1822Asp	missense
NM_001127510.3:c.5465T>A	NP_001120982.1:p.Val1822Asp	missense
NM_001127511.3:c.5411T>A	NP_001120983.2:p.Val1804Asp	missense
NM_001354895.2:c.5465T>A	NP_001341824.1:p.Val1822Asp	missense
NM_001354896.2:c.5519T>A	NP_001341825.1:p.Val1840Asp	missense
NM_001354897.2:c.5495T>A	NP_001341826.1:p.Val1832Asp	missense
NM_001354898.2:c.5390T>A	NP_001341827.1:p.Val1797Asp	missense
NM_001354899.2:c.5381T>A	NP_001341828.1:p.Val1794Asp	missense
NM_001354900.2:c.5342T>A	NP_001341829.1:p.Val1781Asp	missense
NM_001354901.2:c.5288T>A	NP_001341830.1:p.Val1763Asp	missense
NM_001354902.2:c.5192T>A	NP_001341831.1:p.Val1731Asp	missense
NM_001354903.2:c.5162T>A	NP_001341832.1:p.Val1721Asp	missense
NM_001354904.2:c.5087T>A	NP_001341833.1:p.Val1696Asp	missense
NM_001354905.2:c.4985T>A	NP_001341834.1:p.Val1662Asp	missense
NM_001354906.2:c.4616T>A	NP_001341835.1:p.Val1539Asp	missense
NC_000005.10:g.112841059T>A
NC_000005.9:g.112176756T>A
NC_000005.8:g.112204655T>A
NG_008481.4:g.153539T>A
LRG_130:g.153539T>A
LRG_130t1:c.5465T>A	LRG_130p1:p.Val1822Asp
	P25054:p.Val1822Asp

... more HGVS ... less HGVS

Protein change

V1804D, V1822D, V1539D, V1696D, V1781D, V1797D, V1662D, V1721D, V1794D, V1731D, V1832D, V1840D, V1763D

Other names

NM_000038.6(APC):c.5465T>A

Canonical SPDI

NC_000005.10:112841058:T:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.13459 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.79483

The Genome Aggregation Database (gnomAD) 0.82042

Exome Aggregation Consortium (ExAC) 0.79810

Trans-Omics for Precision Medicine (TOPMed) 0.84110

1000 Genomes Project 0.86542

1000 Genomes Project 30x 0.86790

The Genome Aggregation Database (gnomAD), exomes 0.77616

The Genome Aggregation Database (gnomAD) 0.82099

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.82626

Links

ClinGen: CA010422 UniProtKB: P25054#VAR_008993 dbSNP: rs459552 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APC		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	16404	16550

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial adenomatous polyposis 1	Benign (6)	reviewed by expert panel	Feb 26, 2023	RCV000020089.22
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Jul 30, 2025	RCV000034393.28
not specified	Benign (9)	criteria provided, multiple submitters, no conflicts	Mar 16, 2016	RCV000035078.43
Familial colorectal cancer	other (1)	no assertion criteria provided	-	RCV000074239.10
Hereditary cancer-predisposing syndrome	Benign (4)	criteria provided, multiple submitters, no conflicts	Jul 10, 2025	RCV000132160.17
APC-Associated Polyposis Disorders	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV000358689.13
Familial multiple polyposis syndrome	Benign (1)	no assertion criteria provided	-	RCV001270286.9
Classic or attenuated familial adenomatous polyposis	Benign (1)	criteria provided, single submitter	Oct 3, 2024	RCV003996112.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Feb 26, 2023) C Contributing to aggregate classification	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)	Familial adenomatous polyposis 1 (Autosomal dominant inheritance)	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel FDA Recognized Database Accession: SCV003836607.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/382336bf-1845-4ef0-9f6d-e061437c0adb Comment: show The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). 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 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000301601.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 06, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	APC-Associated Polyposis Disorders	Illumina Laboratory Services, Illumina Accession: SCV000452027.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 27, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000681741.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Benign (Jul 07, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial adenomatous polyposis 1	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004017472.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Feb 04, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial adenomatous polyposis 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000647588.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 16, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jul 30, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602499.11 First in ClinVar: Apr 12, 2013 Last updated: Jan 24, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Oct 15, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial adenomatous polyposis 1	SIB Swiss Institute of Bioinformatics Accession: SCV000883261.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Comment: show This variant is interpreted as Benign for Familial adenomatous polyposis 1. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (Mar 03, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001888577.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: show This variant is associated with the following publications: (PMID: 24728327, 27347161, 27153395, 9950360, 18343606, 20027139, 21859464, 24599579, 21995949, 20510605, 20149637, 16569251, 16574953, 22703879) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Nov 13, 2014) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000187234.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: show This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Oct 03, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Classic or attenuated familial adenomatous polyposis (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004838056.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 136365 Zygosity: Homozygote, Hemizygote, Single Heterozygote

Benign (Mar 16, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not specified	Eurofins Ntd Llc (ga) Accession: SCV000109828.9 First in ClinVar: Jan 22, 2014 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APC Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 70 Zygosity: Homozygote, Single Heterozygote Sex: mixed

Benign (Jul 10, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	GeneKor MSA Accession: SCV006311394.1 First in ClinVar: Aug 30, 2025 Last updated: Aug 30, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jul 24, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Adenomatous polyposis coli	Pathway Genomics Accession: SCV000189854.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (3) PubMed: 23159591‚ 23576677‚ 24039736 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257016.2 First in ClinVar: Nov 20, 2015 Last updated: Aug 27, 2017	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Mar 01, 2008) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058718.4 First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017	Publications: PubMed (1) PubMed: 14616385 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 28

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	Familial multiple polyposis syndrome	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591191.2 First in ClinVar: Aug 27, 2017 Last updated: Dec 19, 2020	Comment: show This p.Val1822Asp variant is not expected to have clinical significance because this residue is not conserved and the variant amino acid (Asp) is present in other mammals such as chimp, macaque, rat and dog as well as some lower evolutionary species, increasing the likelihood that this is a benign variant. In addition, it is not located near a splice junction, and is listed in dbSNP (id:rs459552) with a minor allele frequency of 0.140 in a Caucasian population. The clinical relevance of this variant is still under debate, since some studies showed that it could act as a low-penetrance allele that increases the risk of developing colorectal cancer (CRC) while others consider it as a common polymorphism without clinical consequences (Picelli_2010_20149637). In summary, based on the above information, the p.Val1822Asp variant is predicted to be benign, but we cannot rule out the possibility that this may be a low-penetrance polymorphic allele that increases risk of CRC. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740132.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919186.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953754.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972943.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Dec 21, 2021) N Not contributing to aggregate classification	no assertion criteria provided	Hereditary cancer-predisposing syndrome	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV002050306.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jul 13, 2012) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043133.2 First in ClinVar: Apr 12, 2013 Last updated: Jun 08, 2025	Publications: PubMed (1) PubMed: 22703879 Comment: show Converted during submission from no known pathogenicity to Benign. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: no more Observation 1 Collection method: research Allele origin: germline Affected status: no Number of individuals with the variant: 510 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less) Platform type: High-Throughput DNA Sequencing Platform name: Illumina GAIIx

other (-) N Not contributing to aggregate classification	no assertion criteria provided	Familial colorectal cancer	Systems Biology Platform Zhejiang California International NanoSystems Institute Accession: SCV000105832.2 First in ClinVar: Oct 31, 2013 Last updated: Jun 08, 2025	Comment: show Converted during submission from cancer to other. (less) Observation: 1 Collection method: not provided Allele origin: unknown Affected status: not provided Observation 1 Collection method: not provided Allele origin: unknown Affected status: not provided

not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided	AllHighlyPenetrant	ITMI Accession: SCV000084185.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation: 7 Observation 1 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Whole_cohort Platform type: next-gen sequencing Platform name: Complete Genomics Observation 2 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African Platform type: next-gen sequencing Platform name: Complete Genomics Observation 3 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African_European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 4 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Central_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 5 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: East_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 6 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 7 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Hispanic Platform Type: next-gen sequencing Platform Name: Complete Genomics

not provided (-) N Not contributing to aggregate classification	no classification provided	Familial adenomatous polyposis 1	GeneReviews Accession: SCV000040395.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 11221825‚ 17556698‚ 20301519 BookShelf: NBK1345 BookShelf: NBK1345 Observation: 1 Collection method: literature only Allele origin: unknown Affected status: not provided Observation 1 Collection method: literature only Allele origin: unknown Affected status: not provided

Comment:

The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). 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 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This p.Val1822Asp variant is not expected to have clinical significance because this residue is not conserved and the variant amino acid (Asp) is present in other mammals such as chimp, macaque, rat and dog as well as some lower evolutionary species, increasing the likelihood that this is a benign variant. In addition, it is not located near a splice junction, and is listed in dbSNP (id:rs459552) with a minor allele frequency of 0.140 in a Caucasian population. The clinical relevance of this variant is still under debate, since some studies showed that it could act as a low-penetrance allele that increases the risk of developing colorectal cancer (CRC) while others consider it as a common polymorphism without clinical consequences (Picelli_2010_20149637). In summary, based on the above information, the p.Val1822Asp variant is predicted to be benign, but we cannot rule out the possibility that this may be a low-penetrance polymorphic allele that increases risk of CRC.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
APC-Associated Polyposis Conditions.	Adam MP	-	2022	PMID: 20301519
Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility.	Picelli S	PloS one	2013	PMID: 24039736
APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis.	Liang J	American journal of epidemiology	2013	PMID: 23576677
APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests.	Kerr SE	The Journal of molecular diagnostics : JMD	2013	PMID: 23159591
The D1822V APC polymorphism interacts with fat, calcium, and fiber intakes in modulating the risk of colorectal cancer in Portuguese persons.	Guerreiro CS	The American journal of clinical nutrition	2007	PMID: 17556698
The concomitant occurrence of multiple epidermal cysts, osteomas and thyroid gland nodules is not diagnostic for Gardner syndrome in the absence of intestinal polyposis: a clinical and genetic report.	Herrmann SM	The British journal of dermatology	2003	PMID: 14616385
A molecular variant of the APC gene at codon 1822: its association with diet, lifestyle, and risk of colon cancer.	Slattery ML	Cancer research	2001	PMID: 11221825
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APC	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/382336bf-1845-4ef0-9f6d-e061437c0adb	-	-	-	-

Text-mined citations for rs459552 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 08, 2026