VCV000042238.50 - ClinVar

NM_000038.6(APC):c.1458T>C (p.Tyr486=)

Germline

Top reviewed classifications are shown here.

Submission summary:

23 submissions

23 submitters

8 conditions

Reviewed by expert panel

Benign

Feb 2023 by ClinGen InSiGH… FDA Recognized Database

for Familial adenomatous polyposis 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.1458T>C (p.Tyr486=)

Variation ID: 42238 Accession: VCV000042238.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112827157 (GRCh38) [ NCBI UCSC ] 5: 112162854 (GRCh37) [ NCBI UCSC ] 5: 112190753 (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	Oct 31, 2013	May 1, 2024	Feb 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.1458T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Tyr486=	synonymous
NM_001127510.3:c.1458T>C	NP_001120982.1:p.Tyr486=	synonymous
NM_001127511.3:c.1404T>C	NP_001120983.2:p.Tyr468=	synonymous
NM_001354895.2:c.1458T>C	NP_001341824.1:p.Tyr486=	synonymous
NM_001354896.2:c.1512T>C	NP_001341825.1:p.Tyr504=	synonymous
NM_001354897.2:c.1488T>C	NP_001341826.1:p.Tyr496=	synonymous
NM_001354898.2:c.1383T>C	NP_001341827.1:p.Tyr461=	synonymous
NM_001354899.2:c.1374T>C	NP_001341828.1:p.Tyr458=	synonymous
NM_001354900.2:c.1335T>C	NP_001341829.1:p.Tyr445=	synonymous
NM_001354901.2:c.1281T>C	NP_001341830.1:p.Tyr427=	synonymous
NM_001354902.2:c.1185T>C	NP_001341831.1:p.Tyr395=	synonymous
NM_001354903.2:c.1155T>C	NP_001341832.1:p.Tyr385=	synonymous
NM_001354904.2:c.1080T>C	NP_001341833.1:p.Tyr360=	synonymous
NM_001354905.2:c.978T>C	NP_001341834.1:p.Tyr326=	synonymous
NM_001354906.2:c.609T>C	NP_001341835.1:p.Tyr203=	synonymous
NC_000005.10:g.112827157T>C
NC_000005.9:g.112162854T>C
NC_000005.8:g.112190753T>C
NG_008481.4:g.139637T>C
LRG_130:g.139637T>C
LRG_130t1:c.1458T>C

... more HGVS ... less HGVS

Protein change

Other names

NM_000038.6(APC):c.1458T>C
p.Tyr486=

Canonical SPDI

NC_000005.10:112827156:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.49002 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.58437

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.46217

The Genome Aggregation Database (gnomAD) 0.46792

Trans-Omics for Precision Medicine (TOPMed) 0.48299

1000 Genomes Project 30x 0.50468

1000 Genomes Project 0.50998

Exome Aggregation Consortium (ExAC) 0.57798

Links

ClinGen: CA005169 dbSNP: rs2229992 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	14981	15119

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.
not specified	Benign (10)	criteria provided, multiple submitters, no conflicts	Mar 16, 2016	RCV000035064.42
Familial colorectal cancer	other (1)	no assertion criteria provided	-	RCV000074147.9
Hereditary cancer-predisposing syndrome	Benign (4)	criteria provided, multiple submitters, no conflicts	Dec 9, 2019	RCV000131423.17
APC-Associated Polyposis Disorders	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV000275522.13
Carcinoma of colon Desmoid disease, hereditary Familial adenomatous polyposis 1 Hepatocellular carcinoma Neoplasm of stomach	Benign (1)	criteria provided, single submitter	Oct 31, 2018	RCV000755636.10
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV001675589.20
Familial adenomatous polyposis 1	Benign (3)	reviewed by expert panel	Feb 19, 2023	RCV003148640.11
Carcinoma of colon	Benign (1)	no assertion criteria provided	-	RCV001353619.9

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.	More information 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 19, 2023)	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1) Method: curation	Familial adenomatous polyposis 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel FDA Recognized Database Accession: SCV003836582.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ceaf12ac-7838-446c-ae16-b4059d1b3f42 Comment: The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele … (more) The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP 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, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022). (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000301587.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001894230.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 30272267)
Benign (Mar 16, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000109810.8 First in ClinVar: Jan 17, 2014 Last updated: Aug 27, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APC Number of individuals with the variant: 52 Sex: mixed
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV002073833.1 First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022	Number of individuals with the variant: 2046 Ethnicity/Population group: Arab Geographic origin: Middle East
Benign (Dec 09, 2019)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002535674.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004017494.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000647179.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Benign (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer Hepatocellular carcinoma Desmoid disease, hereditary Familial adenomatous polyposis 1 Familial adenomatous polyposis 1 Gastric cancer Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000883033.1 First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	APC-Associated Polyposis Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000451988.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	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 … (more) 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)
Benign (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000681463.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602510.9 First in ClinVar: Aug 27, 2017 Last updated: Feb 20, 2024
Benign (Oct 24, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186404.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 25992589‚ 26493165 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 … (more) 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)
cancer (-)	no assertion criteria provided Method: not provided	Familial colorectal cancer Affected status: not provided Allele origin: unknown	Systems Biology Platform Zhejiang California International NanoSystems Institute Accession: SCV000105740.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013	Comment: Converted during submission to other.
Benign (Mar 01, 2008)	no assertion criteria provided Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058704.4 First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017	Number of individuals with the variant: 24
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977893.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000256922.2 First in ClinVar: Nov 20, 2015 Last updated: Aug 27, 2017
Benign (-)	no assertion criteria provided Method: clinical testing	Carcinoma of colon Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000591074.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The c.1458T>C, p.Tyr486Tyr silent variant, located in exon 12 of APC, is not expected to have clinical significance because it does not alter an amino … (more) The c.1458T>C, p.Tyr486Tyr silent variant, located in exon 12 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs_id:rs2229992) with a minor allele frequency of 0.46. Based on the above information, this is a likely benign variant. (less) Number of individuals with the variant: 1
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744287.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918098.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	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: SCV001957590.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	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: SCV001970515.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (Dec 21, 2021)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV002050299.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
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Comment:

The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP 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, BP4, BP7 (VCEP specifications Version 1.0, 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:

The c.1458T>C, p.Tyr486Tyr silent variant, located in exon 12 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs_id:rs2229992) with a minor allele frequency of 0.46. Based on the above information, this is a likely benign variant.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
GREM1 and POLE variants in hereditary colorectal cancer syndromes.	Rohlin A	Genes, chromosomes & cancer	2016	PMID: 26493165
GREM1 germline mutation screening in Ashkenazi Jewish patients with familial colorectal cancer.	Laitman Y	Genetics research	2015	PMID: 25992589
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APC	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ceaf12ac-7838-446c-ae16-b4059d1b3f42	-	-	-	-

Text-mined citations for rs2229992 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000038.6(APC):c.1458T>C (p.Tyr486=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2229992 ...