ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4360A>G (p.Lys1454Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(1); Benign(9); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.4360A>G (p.Lys1454Glu)
Variation ID: 127295 Accession: VCV000127295.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112839954 (GRCh38) [ NCBI UCSC ] 5: 112175651 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 6, 2014 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.4360A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Lys1454Glu missense NM_001127510.3:c.4360A>G NP_001120982.1:p.Lys1454Glu missense NM_001127511.3:c.4306A>G NP_001120983.2:p.Lys1436Glu missense NM_001354895.2:c.4360A>G NP_001341824.1:p.Lys1454Glu missense NM_001354896.2:c.4414A>G NP_001341825.1:p.Lys1472Glu missense NM_001354897.2:c.4390A>G NP_001341826.1:p.Lys1464Glu missense NM_001354898.2:c.4285A>G NP_001341827.1:p.Lys1429Glu missense NM_001354899.2:c.4276A>G NP_001341828.1:p.Lys1426Glu missense NM_001354900.2:c.4237A>G NP_001341829.1:p.Lys1413Glu missense NM_001354901.2:c.4183A>G NP_001341830.1:p.Lys1395Glu missense NM_001354902.2:c.4087A>G NP_001341831.1:p.Lys1363Glu missense NM_001354903.2:c.4057A>G NP_001341832.1:p.Lys1353Glu missense NM_001354904.2:c.3982A>G NP_001341833.1:p.Lys1328Glu missense NM_001354905.2:c.3880A>G NP_001341834.1:p.Lys1294Glu missense NM_001354906.2:c.3511A>G NP_001341835.1:p.Lys1171Glu missense NC_000005.10:g.112839954A>G NC_000005.9:g.112175651A>G NG_008481.4:g.152434A>G LRG_130:g.152434A>G LRG_130t1:c.4360A>G - Protein change
- K1454E, K1436E, K1328E, K1413E, K1426E, K1363E, K1429E, K1464E, K1472E, K1294E, K1171E, K1353E, K1395E
- Other names
- p.K1454E:AAA>GAA
- Canonical SPDI
- NC_000005.10:112839953:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00080 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00054
The Genome Aggregation Database (gnomAD), exomes 0.00060
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00109
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00246
The Genome Aggregation Database (gnomAD) 0.00271
Trans-Omics for Precision Medicine (TOPMed) 0.00294
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 | ||
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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. |
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APC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
14583 | 14717 |
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. |
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Benign (3) |
criteria provided, multiple submitters, no conflicts
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Nov 25, 2020 | RCV000115092.18 | |
Uncertain significance (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148365.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2015 | RCV000238996.10 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000264340.13 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 16, 2016 | RCV000586737.13 | |
Likely benign (1) |
no assertion criteria provided
|
- | RCV001270348.9 | |
Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000200964.30 | |
Benign (1) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000987572.14 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV003650370.1 |
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. |
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Likely benign
(Sep 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694052.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The APC c.4360A>G (p.Lys1454Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. … (more)
Variant summary: The APC c.4360A>G (p.Lys1454Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant is not located in any known domain/repeat (InterPro). This variant was found in 68/123380 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0053867 (56/10396). This frequency is about 75 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In literature, the variant has also been reported in patients of various cancer phenotypes (such as FAP, prostate cancer, hepatic cancer, CRC, bladder cancer and B-cell lymphoma) including somatic occurrences, however, without strong evidence for causality. One functional study showed that this variant has a normal effect in an in vitro beta-cateninregulated transcription (CRT) assay (Azzopardi_2008). Multiple clinical labs have classified this variant as benign/likely benign (3 labs) to uncertain significance (1 lab and 1 database). Taken together, this variant has currently been classified as a Likely Benign. (less)
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Benign
(May 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149001.13
First in ClinVar: May 17, 2014 Last updated: Oct 09, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Mar 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902616.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Benign
(Nov 25, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002532048.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Jan 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186657.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
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)
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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APC-Associated Polyposis Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000452011.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Aug 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000538293.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency high for disorder; multiple papers question pathogenicity (less)
Method: Genome/Exome Filtration
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Benign
(Jun 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805408.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
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Likely benign
(Sep 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Specified
Affected status: unknown
Allele origin:
germline
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Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV000864337.1
First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 |
Comment:
BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration … (more)
BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). (less)
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136911.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Jul 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069704.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Oct 13, 2015)
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criteria provided, single submitter
Method: clinical testing
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Adenomatous polyposis coli
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000297022.3
First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022 |
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Benign
(Jan 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047313.2
First in ClinVar: Jan 03, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004025062.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000153821.14
First in ClinVar: Jun 03, 2014 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Colorectal adenoma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190057.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Familial colorectal cancer
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001450573.1 First in ClinVar: Dec 16, 2020 Last updated: Dec 16, 2020 |
Comment:
The APC p.Lys1454Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was … (more)
The APC p.Lys1454Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Conflicting interpretations of pathogencitiy. Benign(6);Likely benign(4);Uncertain significance(1) ) and Cosmic (Reported x5 Confirmed somatic, identified in tumor tissue from urinary tract (x3), prostate, and haematopoetic and lymphoid tissue) databases. The variant was identified in control databases in 228 of 282622 chromosomes at a frequency of 0.0008067 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 206 of 24960 chromosomes (freq: 0.008253), Latino in 16 of 35416 chromosomes (freq: 0.000452), Other in 3 of 7214 chromosomes (freq: 0.000416), European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004), European (non-Finnish) in 2 of 128990 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys1454 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One functional study found that the p.Lys1454Glu variant suppresses beta-catenin mediated transcription at a level similar to wild-type APC in a cell culture assay, and is therefore predicted to have no effect on APC protein function (Azzopardi_2008_PMID:18199528). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Molecular profiling of infiltrating urothelial carcinoma of bladder and nonbladder origin. | Millis SZ | Clinical genitourinary cancer | 2015 | PMID: 25178641 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
APC germline mutations in families with familial adenomatous polyposis. | De Queiroz Rossanese LB | Oncology reports | 2013 | PMID: 23970361 |
Genetic heterogeneity of diffuse large B-cell lymphoma. | Zhang J | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23292937 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
The mutational landscape of lethal castration-resistant prostate cancer. | Grasso CS | Nature | 2012 | PMID: 22722839 |
Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? | Minde DP | Molecular cancer | 2011 | PMID: 21859464 |
Somatic mutations of adenomatous polyposis coli gene and nuclear b-catenin accumulation have prognostic significance in invasive urothelial carcinomas: evidence for Wnt pathway implication. | Kastritis E | International journal of cancer | 2009 | PMID: 18844223 |
Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. | Azzopardi D | Cancer research | 2008 | PMID: 18199528 |
Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway. | Torbenson M | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2002 | PMID: 11904335 |
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Text-mined citations for rs111866410 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.