ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.4332A>T (p.Gln1444His)
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(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000038.6(APC):c.4332A>T (p.Gln1444His)
Variation ID: 411562 Accession: VCV000411562.61
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112839926 (GRCh38) [ NCBI UCSC ] 5: 112175623 (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 Oct 10, 2018 Jun 17, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000038.6:c.4332A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.Gln1444His missense NM_001127510.3:c.4332A>T NP_001120982.1:p.Gln1444His missense NM_001127511.3:c.4278A>T NP_001120983.2:p.Gln1426His missense NM_001354895.2:c.4332A>T NP_001341824.1:p.Gln1444His missense NM_001354896.2:c.4386A>T NP_001341825.1:p.Gln1462His missense NM_001354897.2:c.4362A>T NP_001341826.1:p.Gln1454His missense NM_001354898.2:c.4257A>T NP_001341827.1:p.Gln1419His missense NM_001354899.2:c.4248A>T NP_001341828.1:p.Gln1416His missense NM_001354900.2:c.4209A>T NP_001341829.1:p.Gln1403His missense NM_001354901.2:c.4155A>T NP_001341830.1:p.Gln1385His missense NM_001354902.2:c.4059A>T NP_001341831.1:p.Gln1353His missense NM_001354903.2:c.4029A>T NP_001341832.1:p.Gln1343His missense NM_001354904.2:c.3954A>T NP_001341833.1:p.Gln1318His missense NM_001354905.2:c.3852A>T NP_001341834.1:p.Gln1284His missense NM_001354906.2:c.3483A>T NP_001341835.1:p.Gln1161His missense NC_000005.10:g.112839926A>T NC_000005.9:g.112175623A>T NG_008481.4:g.152406A>T LRG_130:g.152406A>T LRG_130t1:c.4332A>T - Protein change
- Q1426H, Q1444H, Q1403H, Q1318H, Q1419H, Q1454H, Q1161H, Q1462H, Q1284H, Q1343H, Q1353H, Q1385H, Q1416H
- Other names
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- Canonical SPDI
- NC_000005.10:112839925:A:T
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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 |
14938 | 15076 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 27, 2023 | RCV000571742.20 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 3, 2023 | RCV001550235.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 31, 2022 | RCV002489079.8 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV002526464.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV004001983.2 |
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. |
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Uncertain significance
(Dec 13, 2021)
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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: SCV002532015.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The APC c.4332A>T (p.Q1444H) variant has been reported in at least one individual with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). It was … (more)
The APC c.4332A>T (p.Q1444H) variant has been reported in at least one individual with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). It was observed in 2/113548 chromosomes of the Non-Finnish European 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 411562). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(May 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer
Hepatocellular carcinoma Desmoid disease, hereditary Familial adenomatous polyposis 1 Familial adenomatous polyposis 1 Gastric cancer Gastric adenocarcinoma and proximal polyposis of the stomach
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782650.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Feb 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001770531.3
First in ClinVar: Aug 07, 2021 Last updated: Nov 11, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25742471, 30309722, 18199528, 25980754) (less)
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Uncertain significance
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175617.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The APC c.4332A>T variant is classified as VUS. The APC c.4332A>T variant is a single nucleotide change in exon 16/16 of the APC gene, which … (more)
The APC c.4332A>T variant is classified as VUS. The APC c.4332A>T variant is a single nucleotide change in exon 16/16 of the APC gene, which is predicted to change the amino acid glutamine at position 1444 in the protein to histidine. This variant was reported in an individual that had a history of Lynch syndrome-associated cancer (PMID: 25980754) Disease causing variants in APC are predominantly truncating variants and this variant is a missense variant which is not located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) (BP1). The variant has been reported in dbSNP (rs748342378) and in the HGMD database: CM1825341. It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 411562). (less)
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Uncertain significance
(Jul 24, 2023)
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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: SCV000552774.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. ClinVar contains an entry for this variant (Variation ID: 411562). This missense change has been observed in individual(s) with clinical features of APC-related conditions (PMID: 25980754). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1444 of the APC protein (p.Gln1444His). (less)
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Uncertain significance
(Jun 27, 2023)
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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: SCV000903927.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with histidine at codon 1444 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with histidine at codon 1444 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 performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 2/251194 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)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Classic or attenuated familial adenomatous polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004837913.1
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)
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Comment:
This missense variant replaces glutamine with histidine at codon 1444 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with histidine at codon 1444 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 2/251194 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: 6
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Likely benign
(Mar 07, 2023)
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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: SCV000667243.6
First in ClinVar: Jan 01, 2018 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)
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Uncertain significance
(Nov 27, 2023)
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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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Baylor Genetics
Accession: SCV005052544.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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 a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Text-mined citations for rs748342378 ...
HelpRecord last updated Sep 17, 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.