ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.3415A>C (p.Lys1139Gln)
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(8); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000038.6(APC):c.3415A>C (p.Lys1139Gln)
Variation ID: 181801 Accession: VCV000181801.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q22.2 5: 112839009 (GRCh38) [ NCBI UCSC ] 5: 112174706 (GRCh37) [ 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 Aug 27, 2017 Sep 16, 2024 Apr 11, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000038.6:c.3415A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Lys1139Gln missense NM_001127510.3:c.3415A>C NP_001120982.1:p.Lys1139Gln missense NM_001127511.3:c.3361A>C NP_001120983.2:p.Lys1121Gln missense NM_001354895.2:c.3415A>C NP_001341824.1:p.Lys1139Gln missense NM_001354896.2:c.3469A>C NP_001341825.1:p.Lys1157Gln missense NM_001354897.2:c.3445A>C NP_001341826.1:p.Lys1149Gln missense NM_001354898.2:c.3340A>C NP_001341827.1:p.Lys1114Gln missense NM_001354899.2:c.3331A>C NP_001341828.1:p.Lys1111Gln missense NM_001354900.2:c.3292A>C NP_001341829.1:p.Lys1098Gln missense NM_001354901.2:c.3238A>C NP_001341830.1:p.Lys1080Gln missense NM_001354902.2:c.3142A>C NP_001341831.1:p.Lys1048Gln missense NM_001354903.2:c.3112A>C NP_001341832.1:p.Lys1038Gln missense NM_001354904.2:c.3037A>C NP_001341833.1:p.Lys1013Gln missense NM_001354905.2:c.2935A>C NP_001341834.1:p.Lys979Gln missense NM_001354906.2:c.2566A>C NP_001341835.1:p.Lys856Gln missense NC_000005.10:g.112839009A>C NC_000005.9:g.112174706A>C NG_008481.4:g.151489A>C LRG_130:g.151489A>C LRG_130t1:c.3415A>C - Protein change
- K1121Q, K1139Q, K1080Q, K1157Q, K979Q, K1013Q, K1038Q, K1111Q, K1114Q, K1149Q, K1048Q, K1098Q, K856Q
- Other names
- p.K1139Q:AAG>CAG
- Canonical SPDI
- NC_000005.10:112839008:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
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 | ||
---|---|---|---|---|---|---|
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 |
14956 | 15094 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 2, 2024 | RCV000159549.25 | |
Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000211910.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2024 | RCV000586988.16 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 1, 2023 | RCV003998412.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 28, 2023 | RCV001818351.11 | |
Likely benign (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV004562323.2 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Apr 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209514.17
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; … (more)
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528) (less)
|
|
Uncertain significance
(Jan 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070056.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the APC gene demonstrated a sequence change, c.3415A>C, in exon 16 that results in an amino acid change, p.Lys1139Gln. This sequence … (more)
DNA sequence analysis of the APC gene demonstrated a sequence change, c.3415A>C, in exon 16 that results in an amino acid change, p.Lys1139Gln. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database with a low population frequency of 0.089% in Ashkenazi Jewish subpopulation (dbSNP rs201550951). The p.Lys1139Gln change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys1139Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys1139Gln change remains unknown at this time. (less)
|
|
Uncertain significance
(Jan 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000681598.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces lysine with glutamine at codon 1139 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces lysine with glutamine at codon 1139 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 10/250914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain Significance
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004839806.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 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)
|
Comment:
This missense variant replaces lysine with glutamine at codon 1139 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces lysine with glutamine at codon 1139 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 10/250914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 8
|
|
Likely benign
(Jan 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000217820.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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)
|
|
Uncertain significance
(Apr 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005045346.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
|
|
Uncertain significance
(Dec 07, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002535516.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
To the best of our knowledge, the APC c.3415A>C (p.K1139Q) variant has not been reported in individuals with APC-related disease. This variant was observed in … (more)
To the best of our knowledge, the APC c.3415A>C (p.K1139Q) variant has not been reported in individuals with APC-related disease. This variant was observed in 9/10062 chromosomes in the Ashkenazi Jewish subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 181801). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
|
|
|
Uncertain significance
(Aug 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694032.2
First in ClinVar: Mar 17, 2018 Last updated: Oct 04, 2023 |
Comment:
Variant summary: APC c.3415A>C (p.Lys1139Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: APC c.3415A>C (p.Lys1139Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250914 control chromosomes in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3415A>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=2) and VUS (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Jun 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222520.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, … (more)
To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00089 (9/10062 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Likely benign
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000282741.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
|
|
Uncertain significance
(-)
|
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: SCV000591140.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Lys1139Gln variant has not been reported in the literature nor previously identified by our laboratory. This residue is conserved in mammals but not in … (more)
The p.Lys1139Gln variant has not been reported in the literature nor previously identified by our laboratory. This residue is conserved in mammals but not in lower organisms, and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. (less)
|
|
click to load more click to collapse |
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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs201550951 ...
HelpRecord last updated Oct 13, 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.