ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.71G>C (p.Arg24Pro)
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>C (p.Arg24Pro)
Variation ID: 9415 Accession: VCV000009415.34
- 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 Apr 4, 2013 Aug 25, 2024 May 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.71G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Arg24Pro missense NM_058195.4:c.194-3549G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001195132.2:c.71G>C NP_001182061.1:p.Arg24Pro missense NM_001363763.2:c.-3-3549G>C intron variant NM_058197.5:c.71G>C NP_478104.2:p.Arg24Pro missense NC_000009.12:g.21974757C>G NC_000009.11:g.21974756C>G NG_007485.1:g.24735G>C LRG_11:g.24735G>C LRG_11t1:c.71G>C LRG_11p1:p.Arg24Pro P42771:p.Arg24Pro - Protein change
- R24P
- Other names
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- Canonical SPDI
- NC_000009.12:21974756:C:G
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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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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. |
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CDKN2A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1260 | 1412 |
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. |
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risk factor (1) |
no assertion criteria provided
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Aug 1, 1998 | RCV000010022.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2024 | RCV000167312.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2022 | RCV000236320.8 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 20, 2023 | RCV000410204.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV000472219.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763193.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2024 | RCV003473077.2 |
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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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 2
Melanoma and neural system tumor syndrome Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893806.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Dec 15, 2020)
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criteria provided, single submitter
Method: research
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Melanoma-pancreatic cancer syndrome
Affected status: no
Allele origin:
germline
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Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478114.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Melanoma-pancreatic cancer syndrome
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499642.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Oct 03, 2022)
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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: SCV000292535.14
First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: impaired binding to CDK4, impaired growth inhibition, and altered cellular localization (Monzon et al., 1998; Becker et al., … (more)
Published functional studies demonstrate a damaging effect: impaired binding to CDK4, impaired growth inhibition, and altered cellular localization (Monzon et al., 1998; Becker et al., 2001; McKenzie et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9516223, 10398427, 9823374, 9699728, 33945383, 29922827, 11595726, 21462282, 23190892, 16234564, 8570179, 9425228, 26845104, 11500805, 26775776, 15945100, 18843795, 26225579, 25356972, 26206375, 15235029, 28830827, 9328469, 15304099, 15146471, 9856841, 10390011, 12072543, 11815963, 21150883, 17218939, 21801156, 16905682, 18363633, 17047042, 26800492, 29506128, 31382929, 34308366, 32482799, 14646620, 30967399, 33050356, 30218143, 27535533, 11556834, 20340136) (less)
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Pathogenic
(Mar 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004234498.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 21, 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: SCV000684536.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces arginine with proline at codon 24 of the CDKN2A … (more)
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces arginine with proline at codon 24 of the CDKN2A (p16INK4A) protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant causes loss of p16INK4A binding to CDK4 and loss of cell cycle inhibition function (PMID: 17909018, 15945100, 19260062, 20340136, 11595726, 18843795). This variant has been reported in over 40 individuals affected with melanoma (PMID: 10390011, 15146471, 16905682, 17047042, 18363633, 21801156, 25780468, 26225579, 26775776, 33050356) and pancreatic cancer (PMID: 15146471, 16905682, 21150883, 25356972). A family study has shown that this variant segregates with melanoma in multiple related individuals (PMID: 9699728). This variant has been identified in 4/236656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Nov 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266063.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
Clinical Features:
melanoma (present) , breast cancer (present)
Age: 50-59 years
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Likely pathogenic
(Jul 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488917.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Apr 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018546.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8570179, 11556834]. Functional studies … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8570179, 11556834]. Functional studies indicate this variant impacts protein function [PMID: 17909018]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Jan 21, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545544.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 24 of the CDKN2A (p16INK4a) protein … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 24 of the CDKN2A (p16INK4a) protein (p.Arg24Pro). This variant is present in population databases (rs104894097, gnomAD 0.004%). This missense change has been observed in individual(s) with pancreatic cancer and multiple primary melanomas (PMID: 8570179, 9699728, 10390011, 15146471, 16905682, 17047042, 18363633, 21150883, 21801156, 25356972, 26225579). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9415). 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 11595726, 15945100, 18843795, 20340136, 23190892). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Melanoma and neural system tumor syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004212524.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(May 22, 2024)
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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: SCV000218160.9
First in ClinVar: Mar 24, 2015 Last updated: Aug 11, 2024 |
Comment:
The p.R24P pathogenic mutation (also known as c.71G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at … (more)
The p.R24P pathogenic mutation (also known as c.71G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 71. The arginine at codon 24 is replaced by proline, an amino acid with dissimilar properties. This alteration has been detected in numerous familial melanoma kindreds with and without pancreatic cancer; in three such families, the alteration co-segregated with disease in 21 out of 23 affected individuals overall (Soufir N et al. Hum. Mol. Genet. 1998 Feb;7(2):209-16; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87; MacKie RM et al. J. Invest. Dermatol. 1998 Aug;111(2):269-72; Newton Bishop JA et al. Br. J. Cancer 1999 Apr;80(1-2):295-300; Holland EA et al. Genes Chromosomes Cancer 1999 Aug; 25(4):339-48; Della Torre G et al. Br. J. Cancer 2001 Sep;85(6):836-44; Stolarova L et al. Biomedicines. 2020 Oct;8(10):404). Functional studies have shown that p.R24P mutants have varying levels of decreased binding affinity to CDK4 while other assays measuring cell cycle arrest and oxidative regulation have demonstrated activity comparable to wild type (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; McKenzie HA et al. Hum. Mutat. 2010 Jun;31(6):692-701; Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133(4):1043-51; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87, Becker TM et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; Jones R et al. Cancer Res. 2007 Oct;67(19):9134-41). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 27, 2022)
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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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196614.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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risk factor
(Aug 01, 1998)
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no assertion criteria provided
Method: literature only
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MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030243.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with multiple primary melanomas (155601), Monzon et al. (1998) identified an arg24-to-pro mutation in the CDKN2A gene. They pointed out that this … (more)
In a patient with multiple primary melanomas (155601), Monzon et al. (1998) identified an arg24-to-pro mutation in the CDKN2A gene. They pointed out that this mutation had previously been reported in melanoma-prone families and was found to cosegregate with cases of melanoma. MacKie et al. (1998) identified this mutation in a U.K. melanoma family. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Melanoma-pancreatic cancer syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Medical Genetics, Medical University Pleven
Accession: SCV004100897.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Indication for testing: breast cancer
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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 Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes. | Stolarova L | Biomedicines | 2020 | PMID: 33050356 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup. | Bruno W | Journal of the American Academy of Dermatology | 2016 | PMID: 26775776 |
Novel CDKN2A mutations in Austrian melanoma patients. | Burgstaller-Muehlbacher S | Melanoma research | 2015 | PMID: 26225579 |
GESPA: classifying nsSNPs to predict disease association. | Khurana JK | BMC bioinformatics | 2015 | PMID: 26206375 |
BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. | Zhen DB | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356972 |
Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom. | Harland M | Hereditary cancer in clinical practice | 2014 | PMID: 25780468 |
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 |
Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. | McWilliams RR | European journal of human genetics : EJHG | 2011 | PMID: 21150883 |
Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. | McKenzie HA | Human mutation | 2010 | PMID: 20340136 |
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 |
CDKN2A/CDK4 molecular study on 155 Italian subjects with familial and/or primary multiple melanoma. | Majore S | Pigment cell & melanoma research | 2008 | PMID: 18363633 |
A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6. | Jones R | Cancer research | 2007 | PMID: 17909018 |
CDKN2A germline mutations in individuals with cutaneous malignant melanoma. | Orlow I | The Journal of investigative dermatology | 2007 | PMID: 17218939 |
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 |
High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. | Goldstein AM | Cancer research | 2006 | PMID: 17047042 |
Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. | Begg CB | Journal of the National Cancer Institute | 2005 | PMID: 16234564 |
The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired. | Becker TM | International journal of cancer | 2005 | PMID: 15945100 |
Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. | Lynch HT | Cancer | 2002 | PMID: 11815963 |
Functional impairment of melanoma-associated p16(INK4a) mutants in melanoma cells despite retention of cyclin-dependent kinase 4 binding. | Becker TM | Clinical cancer research : an official journal of the American Association for Cancer Research | 2001 | PMID: 11595726 |
CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation. | Della Torre G | British journal of cancer | 2001 | PMID: 11556834 |
CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. | Holland EA | Genes, chromosomes & cancer | 1999 | PMID: 10398427 |
Mutation testing in melanoma families: INK4A, CDK4 and INK4D. | Newton Bishop JA | British journal of cancer | 1999 | PMID: 10390011 |
CDKN2A germline mutations in U.K. patients with familial melanoma and multiple primary melanomas. | MacKie RM | The Journal of investigative dermatology | 1998 | PMID: 9699728 |
CDKN2A mutations in multiple primary melanomas. | Monzon J | The New England journal of medicine | 1998 | PMID: 9516223 |
Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. | Soufir N | Human molecular genetics | 1998 | PMID: 9425228 |
Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds. | Holland EA | Oncogene | 1995 | PMID: 8570179 |
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Text-mined citations for rs104894097 ...
HelpRecord last updated Sep 29, 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.