ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.250G>T (p.Asp84Tyr)
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.
Pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000077.5(CDKN2A):c.250G>T (p.Asp84Tyr)
Variation ID: 376306 Accession: VCV000376306.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21971109 (GRCh38) [ NCBI UCSC ] 9: 21971108 (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 Aug 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.250G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Asp84Tyr missense NM_058195.4:c.293G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478102.2:p.Arg98Leu missense NM_001195132.2:c.250G>T NP_001182061.1:p.Asp84Tyr missense NM_001363763.2:c.97G>T NP_001350692.1:p.Asp33Tyr missense NM_058197.5:c.*173G>T 3 prime UTR NC_000009.12:g.21971109C>A NC_000009.11:g.21971108C>A NG_007485.1:g.28383G>T LRG_11:g.28383G>T LRG_11t1:c.250G>T LRG_11p1:p.Asp84Tyr - Protein change
- D84Y, R98L, D33Y
- Other names
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- Canonical SPDI
- NC_000009.12:21971108: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
1215 | 1371 |
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 | RCV000419046.1 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 20, 2022 | RCV000584237.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV001239054.7 |
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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Uncertain significance
(Feb 25, 2020)
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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: SCV000689596.4
First in ClinVar: Feb 19, 2018 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces aspartic acid with tyrosine at codon 84 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious … (more)
This missense variant replaces aspartic acid with tyrosine at codon 84 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has reported this variant to have no detectable binding to CDK4 and CDK6 in vitro (PMID: 10498896). This variant has been reported in an affected member of a Spanish cutaneous malignant melanoma family, however, segregation with two other affected members could not be examined (PMID: 10874641). The variant also has been detected in two affected members of a melanoma-prone family and at least two additional carriers whose cancer spectrum are not consistent with CDKN2A-associated cancers (Color internal data and communication with external laboratories). This variant has been identified in 1/231524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Two different missense variants, p.Asp84Ala and p.Asp84Asn, have conflicting reports between likely pathogenic and uncertain significance in ClinVar (variation ID: 142882, 229806). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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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Pathogenic
(Dec 20, 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: SCV001176643.4
First in ClinVar: Mar 16, 2020 Last updated: Apr 15, 2023 |
Comment:
The p.D84Y pathogenic mutation (also known as c.250G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at … (more)
The p.D84Y pathogenic mutation (also known as c.250G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 250. The aspartic acid at codon 84 is replaced by tyrosine, an amino acid with highly dissimilar properties. Functional studies demonstrate that this alteration results in impaired binding with CDK4 and CDK6 (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Ruas M et al. Oncogene 1999 Sep;18(39):5423-34). Further, this alteration occurs at a mutational hotspot, with p.D84N and p.D84H also demonstrating impaired binding (Ruas M et al. Oncogene 1999 Sep;18(39):5423-34). Structural analysis indicates that this alteration dramatically alters the electrostatic character of the CDK-binding surface of p16, resulting in a severe pertubation of the protein structure which likely leads to misfolding and loss of binding (Ruas M et al. Oncogene 1999 Sep;18(39):5423-34; Rajasekaran R et al. Biochimie 2008 Oct;90(10):1523-9; Ambry internal data). In addition, this alteration has been reported in multiple families with familial melanoma, including one family with three individuals with cutaneous malignant melanoma and two individuals with dysplastic nevi (Ambry internal data; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11; Ruiz A et al. J. Med. Genet. 1999 Jun;36(6):490-3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Uncertain significance
(Aug 22, 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: SCV001411899.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD … (more)
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 10360174, 10498896). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 376306). This variant is also known as c.293G>T (p.Arg98Leu) in the CDKN2A (p14AFR) transcript. This missense change has been observed in individual(s) with melanoma (PMID: 10874641, 21462282, 26650189, 26681309). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Tyr). 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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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: SCV000505632.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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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Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. | Puig S | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681309 |
Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. | Potrony M | JAMA dermatology | 2016 | PMID: 26650189 |
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family. | Maubec E | Journal of the American Academy of Dermatology | 2012 | PMID: 22841127 |
Classifying variants of CDKN2A using computational and laboratory studies. | Miller PJ | Human mutation | 2011 | PMID: 21462282 |
A flexible multiplex bead-based assay for detecting germline CDKN2A and CDK4 variants in melanoma-prone kindreds. | Lang JM | The Journal of investigative dermatology | 2011 | PMID: 21085193 |
In silico analysis of structural and functional consequences in p16INK4A by deleterious nsSNPs associated CDKN2A gene in malignant melanoma. | Rajasekaran R | Biochimie | 2008 | PMID: 18573309 |
Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia. | Ruiz A | Journal of medical genetics | 1999 | PMID: 10874641 |
Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information. | Ruas M | Oncogene | 1999 | PMID: 10498896 |
Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. | Zhang Y | Molecular cell | 1999 | PMID: 10360174 |
The CDKN2A (p16) gene and human cancer. | Foulkes WD | Molecular medicine (Cambridge, Mass.) | 1997 | PMID: 9132280 |
http://docm.genome.wustl.edu/variants/ENST00000361570:c.416G>T | - | - | - | - |
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Text-mined citations for rs11552822 ...
HelpRecord last updated Feb 20, 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.