This variant is denoted APC c.1279C>A at the cDNA level, p.His427Asn (H427N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC His427Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC His427Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_000038.6(APC):c.1279C>A (p.His427Asn)
Germline
Classification
Help
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.
(8)
Help
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
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000038.6(APC):c.1279C>A (p.His427Asn)
Variation ID: 127276 Accession: VCV000127276.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q22.2 5: 112819311 (GRCh38) [ NCBI UCSC ] 5: 112155008 (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 May 29, 2016 Aug 11, 2024 Apr 30, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000038.6:c.1279C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000029.2:p.His427Asn missense NM_001127510.3:c.1279C>A NP_001120982.1:p.His427Asn missense NM_001127511.3:c.1225C>A NP_001120983.2:p.His409Asn missense NM_001354895.2:c.1279C>A NP_001341824.1:p.His427Asn missense NM_001354896.2:c.1279C>A NP_001341825.1:p.His427Asn missense NM_001354897.2:c.1309C>A NP_001341826.1:p.His437Asn missense NM_001354898.2:c.1204C>A NP_001341827.1:p.His402Asn missense NM_001354899.2:c.1195C>A NP_001341828.1:p.His399Asn missense NM_001354900.2:c.1102C>A NP_001341829.1:p.His368Asn missense NM_001354901.2:c.1102C>A NP_001341830.1:p.His368Asn missense NM_001354902.2:c.1006C>A NP_001341831.1:p.His336Asn missense NM_001354903.2:c.976C>A NP_001341832.1:p.His326Asn missense NM_001354904.2:c.901C>A NP_001341833.1:p.His301Asn missense NM_001354905.2:c.799C>A NP_001341834.1:p.His267Asn missense NM_001354906.2:c.430C>A NP_001341835.1:p.His144Asn missense NC_000005.10:g.112819311C>A NC_000005.9:g.112155008C>A NG_008481.4:g.131791C>A LRG_130:g.131791C>A LRG_130t1:c.1279C>A - Protein change
- H427N, H409N, H267N, H326N, H399N, H402N, H144N, H301N, H368N, H336N, H437N
- Other names
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p.H427N:CAT>AAT
- Canonical SPDI
- NC_000005.10:112819310:C:A
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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.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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 |
14984 | 15122 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000115068.18 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 30, 2024 | RCV000708636.16 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 10, 2018 | RCV000766425.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 23, 2023 | RCV004562254.2 |
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
(Dec 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000148977.11
First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted APC c.1279C>A at the cDNA level, p.His427Asn (H427N) at the protein level, and results in the change of a Histidine to … (more)
This variant is denoted APC c.1279C>A at the cDNA level, p.His427Asn (H427N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC His427Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC His427Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
|
|
|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821807.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
|
Uncertain significance
(Dec 27, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002533902.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
To the best of our knowledge, the APC c.1279C>A (p.H427N) variant has not been reported in individuals with APC-related disease. It was observed in 3/113184 … (more)
To the best of our knowledge, the APC c.1279C>A (p.H427N) variant has not been reported in individuals with APC-related disease. It was observed in 3/113184 chromosomes of the European (non-Finnish) 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: 127276). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. 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)
|
|
|
|
Uncertain significance
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550579.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
|
|
|
Uncertain significance
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000647167.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 127276). In summary, the available evidence is currently insufficient to determine the role of this variant … (more)
ClinVar contains an entry for this variant (Variation ID: 127276). 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. This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant is present in population databases (rs587779781, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 427 of the APC protein (p.His427Asn). (less)
|
|
|
Uncertain significance
(Apr 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002686782.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.H427N variant (also known as c.1279C>A), located in coding exon 9 of the APC gene, results from a C to A substitution at nucleotide … (more)
The p.H427N variant (also known as c.1279C>A), located in coding exon 9 of the APC gene, results from a C to A substitution at nucleotide position 1279. The histidine at codon 427 is replaced by asparagine, an amino acid with similar properties. This variant was reported as a variant of unknown significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
|
|
|
Uncertain significance
(Jan 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600040.2
First in ClinVar: May 29, 2016 Last updated: Jan 01, 2022 |
|
|
|
Uncertain significance
(Dec 11, 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: SCV001358307.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces histidine with asparagine at codon 427 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces histidine with asparagine at codon 427 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250682 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)
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 127276). 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. This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant is present in population databases (rs587779781, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 427 of the APC protein (p.His427Asn).
Comment:
The p.H427N variant (also known as c.1279C>A), located in coding exon 9 of the APC gene, results from a C to A substitution at nucleotide position 1279. The histidine at codon 427 is replaced by asparagine, an amino acid with similar properties. This variant was reported as a variant of unknown significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant remains unclear.
Comment:
This missense variant replaces histidine with asparagine at codon 427 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250682 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.
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:
This variant is denoted APC c.1279C>A at the cDNA level, p.His427Asn (H427N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC His427Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC His427Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Comment:
ClinVar contains an entry for this variant (Variation ID: 127276). 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. This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant is present in population databases (rs587779781, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 427 of the APC protein (p.His427Asn).
Comment:
The p.H427N variant (also known as c.1279C>A), located in coding exon 9 of the APC gene, results from a C to A substitution at nucleotide position 1279. The histidine at codon 427 is replaced by asparagine, an amino acid with similar properties. This variant was reported as a variant of unknown significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant remains unclear.
Comment:
This missense variant replaces histidine with asparagine at codon 427 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250682 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Text-mined citations for rs587779781 ...
HelpThese 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
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.