ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.71G>A (p.Arg24Gln)
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.71G>A (p.Arg24Gln)
Variation ID: 406714 Accession: VCV000406714.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21974757 (GRCh38) [ NCBI UCSC ] 9: 21974756 (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 Jan 1, 2018 Feb 20, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.71G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Arg24Gln missense NM_058195.4:c.194-3549G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001195132.2:c.71G>A NP_001182061.1:p.Arg24Gln missense NM_001363763.2:c.-3-3549G>A intron variant NM_058197.5:c.71G>A NP_478104.2:p.Arg24Gln missense NC_000009.12:g.21974757C>T NC_000009.11:g.21974756C>T NG_007485.1:g.24735G>A LRG_11:g.24735G>A LRG_11t1:c.71G>A LRG_11p1:p.Arg24Gln - Protein change
- R24Q
- Other names
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- Canonical SPDI
- NC_000009.12:21974756: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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Uncertain significance (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV000473279.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000566208.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 3, 2019 | RCV001283960.1 |
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
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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
(Oct 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469490.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Nov 06, 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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Ambry Genetics
Accession: SCV000673239.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R24Q variant (also known as c.71G>A), located in coding exon 1 of the CDKN2A gene, results from a G to A substitution at nucleotide … (more)
The p.R24Q variant (also known as c.71G>A), located in coding exon 1 of the CDKN2A gene, results from a G to A substitution at nucleotide position 71. The arginine at codon 24 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in individuals with multiple primary melanomas (Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Kannengiesser C et al. Hum. Mutat., 2009 Apr;30:564-74), but also in unaffected individuals (internal data). This variant was reported to impair the cell cycle regulatory capacity of p16 while leaving the oxidative function of the protein intact in one functional study (Jenkins NC et al. J. Invest. Dermatol., 2013 Apr;133:1043-51). However, other functional studies have reported this variant as neutral as assessed by CDK4 binding and cellular proliferation in primary human diploid fibroblasts (Kannengiesser C et al. Hum. Mutat., 2009 Apr;30:564-74) and based on in vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H. et al. Elife, 2022 01;11). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 01, 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: SCV001349024.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 24 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces arginine with glutamine at codon 24 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Some functional studies have shown the mutant protein to exhibit near normal CDK4 binding activity and cell cycle control activity (PMID: 19260062, 35001868), while other study has shown a significant loss of cell cycle control activity (PMID: 23190892). This variant has been observed in two individuals affected with multiple primary melanomas (PMID: 19260062, 21462282). This variant has been identified in 3/236656 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
(Jan 02, 2024)
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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: SCV000545536.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the CDKN2A (p16INK4a) protein … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the CDKN2A (p16INK4a) protein (p.Arg24Gln). This variant is present in population databases (rs104894097, gnomAD 0.003%). This missense change has been observed in individual(s) with multiple primary melanomas (PMID: 19260062, 21462282). ClinVar contains an entry for this variant (Variation ID: 406714). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDKN2A (p16INK4a) function (PMID: 19260062, 23190892). This variant disrupts the p.Arg24 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9699728, 9856841, 15146471, 17909018, 18843795, 21801156). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)
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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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Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance. | Kimura H | eLife | 2022 | PMID: 35001868 |
Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI. | Carraro M | Human mutation | 2017 | PMID: 28440912 |
Familial melanoma-associated mutations in p16 uncouple its tumor-suppressor functions. | Jenkins NC | The Journal of investigative dermatology | 2013 | PMID: 23190892 |
Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma. | Nikolaou V | The British journal of dermatology | 2011 | PMID: 21801156 |
Classifying variants of CDKN2A using computational and laboratory studies. | Miller PJ | Human mutation | 2011 | PMID: 21462282 |
Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients. | Kannengiesser C | Human mutation | 2009 | PMID: 19260062 |
p16INK4a-induced senescence is disabled by melanoma-associated mutations. | Haferkamp S | Aging cell | 2008 | PMID: 18843795 |
A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6. | Jones R | Cancer research | 2007 | PMID: 17909018 |
Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds. | Fargnoli MC | The Journal of investigative dermatology | 1998 | PMID: 9856841 |
CDKN2A germline mutations in U.K. patients with familial melanoma and multiple primary melanomas. | MacKie RM | The Journal of investigative dermatology | 1998 | PMID: 9699728 |
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Text-mined citations for rs104894097 ...
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.