ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.330G>A (p.Trp110Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000077.5(CDKN2A):c.330G>A (p.Trp110Ter)
Variation ID: 376303 Accession: VCV000376303.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21971029 (GRCh38) [ NCBI UCSC ] 9: 21971028 (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 Mar 8, 2017 Feb 14, 2024 May 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.330G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Trp110Ter nonsense NM_058195.4:c.373G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478102.2:p.Gly125Arg missense NM_000077.4:c.330G>A NM_001195132.2:c.330G>A NP_001182061.1:p.Trp110Ter nonsense NM_001363763.2:c.177G>A NP_001350692.1:p.Trp59Ter nonsense NM_058197.5:c.*253G>A 3 prime UTR NC_000009.12:g.21971029C>T NC_000009.11:g.21971028C>T NG_007485.1:g.28463G>A LRG_11:g.28463G>A - Protein change
- G125R, W110*, W59*
- Other names
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- Canonical SPDI
- NC_000009.12:21971028:C: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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CDKN2A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1216 | 1365 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Likely pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000432172.1 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 30, 2019 | RCV001255669.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 13, 2022 | RCV002323583.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2023 | RCV002524693.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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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Pathogenic
(Sep 13, 2022)
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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: SCV002607223.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.W110* variant (also known as c.330G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide … (more)
The p.W110* variant (also known as c.330G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 330. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This alteration has been detected in several melanoma patients, including a Greek patient diagnosed with multiple primary melanomas (Stratigos AJ et al. J Invest Dermatol. 2006 Feb;126:399-401; Nikolaou V et al. Br J Dermatol. 2011 Dec;165:1219-22; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration demonstrated reduced Cdk binding activity (Parry D et al. Mol Cell Biol. 1996 Jul;16:3844-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial melanoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003440778.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its … (more)
For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. Experimental studies have shown that this premature translational stop signal affects CDKN2A (p16INK4a) function (PMID: 8668202). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 376303). This variant is also known as c.373G>A (p.Gly125Arg) in CDKN2A (p14ARF) transcript. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 16374456). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp110*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. (less)
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Pathogenic
(Mar 16, 2022)
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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: SCV004361303.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/books/NBK7030/). This variant changes 1 nucleotide in exon 2 of the CDKN2A (p16INK4A) gene, … (more)
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/books/NBK7030/). This variant changes 1 nucleotide in exon 2 of the CDKN2A (p16INK4A) gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product missing the C-terminal sequence that encodes ankyrin repeat 4. This variant has been reported in two individuals affected with melanoma in the literature (PMID: 16374456, 21801156). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505628.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Apr 30, 2019)
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no assertion criteria provided
Method: research
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Lip and oral cavity carcinoma
Affected status: yes
Allele origin:
somatic
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Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432234.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
Number of individuals with the variant: 3
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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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Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma. | Nikolaou V | The British journal of dermatology | 2011 | PMID: 21801156 |
Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. | Goldstein AM | Journal of medical genetics | 2007 | PMID: 16905682 |
Germline CDKN2A mutations among Greek patients with early-onset and multiple primary cutaneous melanoma. | Stratigos AJ | The Journal of investigative dermatology | 2006 | PMID: 16374456 |
Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma. | Parry D | Molecular and cellular biology | 1996 | PMID: 8668202 |
http://docm.genome.wustl.edu/variants/ENST00000446177:c.330G>A | - | - | - | - |
Text-mined citations for rs121913389 ...
HelpRecord last updated Apr 06, 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.