ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.95T>C (p.Leu32Pro)
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.95T>C (p.Leu32Pro)
Variation ID: 236992 Accession: VCV000236992.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21974733 (GRCh38) [ NCBI UCSC ] 9: 21974732 (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 May 1, 2024 Mar 10, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.95T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Leu32Pro missense NM_058195.4:c.194-3525T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001195132.2:c.95T>C NP_001182061.1:p.Leu32Pro missense NM_001363763.2:c.-3-3525T>C intron variant NM_058197.5:c.95T>C NP_478104.2:p.Leu32Pro missense NC_000009.12:g.21974733A>G NC_000009.11:g.21974732A>G NG_007485.1:g.24759T>C LRG_11:g.24759T>C LRG_11t1:c.95T>C LRG_11p1:p.Leu32Pro P42771:p.Leu32Pro - Protein change
- L32P
- Other names
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- Canonical SPDI
- NC_000009.12:21974732:A: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
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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 |
1246 | 1398 |
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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 10, 2021 | RCV000234305.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 26, 2016 | RCV000561506.3 |
Submissions - Germline
Classification
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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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Pathogenic
(Aug 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cutaneous melanoma
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917149.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: CDKN2A c.95T>C (p.Leu32Pro) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five … (more)
Variant summary: CDKN2A c.95T>C (p.Leu32Pro) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 239900 control chromosomes (gnomAD). The variant, c.95T>C, has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Jouenne_2016, Jovanovic_2010, Box_2001, McKenzie_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (McKenzie_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 10, 2021)
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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: SCV000283452.8
First in ClinVar: Jul 03, 2016 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic Experimental studies have shown that this missense change interferes with the interaction between p16INK4a and its binding partners CDK4 and CDK6 (PMID: 20340136, 19712690). This variant has been reported in patients and families affected with melanoma and pancreatic cancer (PMID: 19759551, 17218939, 16905682, 20340136, 17047042, 28592523).  It has been shown to segregate with disease in one family (PMID: 8595405). ClinVar contains an entry for this variant (Variation ID: 236992). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 32 of the CDKN2A (p16INK4a) protein (p.Leu32Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. (less)
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Likely pathogenic
(Feb 26, 2016)
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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: SCV000673241.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.L32P variant (also known as c.95T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide … (more)
The p.L32P variant (also known as c.95T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide position 95. The leucine at codon 32 is replaced by proline, an amino acid with similar properties. This variant has been reported in numerous individuals with a personal and/or family history of cutaneous melanoma (Aitken J et al, J. Natl. Cancer Inst. 1999 Mar; 91(5):446-52; Begg CB et al, J. Natl. Cancer Inst. 2005 Oct; 97(20):1507-15; Berwick M et al, Cancer Epidemiol. Biomarkers Prev. 2006 Aug; 15(8):1520-5; Bishop DT et al, J. Natl. Cancer Inst. 2002 Jun; 94(12):894-903; Goldstein AM et al, Cancer Res. 2006 Oct; 66(20):9818-28; Goldstein AM et al, J. Med. Genet. 2007 Feb; 44(2):99-10; Jovanovic B et al, J. Invest. Dermatol. 2010 Feb; 130(2):618-20; Orlow I et al, J. Invest. Dermatol. 2007 May; 127(5):1234-43). Further, a functional analysis of the p.L32P variant has demonstrated abolished CDK4 binding capability (McKenzie HA et al, Hum. Mutat. 2010 Jun; 31(6):692-701). 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 majority of available evidence to date, this variant is likely to be pathogenic. (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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Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. | Jouenne F | Journal of medical genetics | 2017 | PMID: 28592523 |
Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. | McKenzie HA | Human mutation | 2010 | PMID: 20340136 |
Coexisting NRAS and BRAF mutations in primary familial melanomas with specific CDKN2A germline alterations. | Jovanovic B | The Journal of investigative dermatology | 2010 | PMID: 19759551 |
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 |
The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study. | Berwick M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2006 | PMID: 16896043 |
Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. | Begg CB | Journal of the National Cancer Institute | 2005 | PMID: 16234564 |
Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
Geographical variation in the penetrance of CDKN2A mutations for melanoma. | Bishop DT | Journal of the National Cancer Institute | 2002 | PMID: 12072543 |
Validation of denaturing high performance liquid chromatography as a rapid detection method for the identification of human INK4A gene mutations. | Orlow I | The Journal of molecular diagnostics : JMD | 2001 | PMID: 11687599 |
MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. | Box NF | American journal of human genetics | 2001 | PMID: 11500805 |
CDKN2A variants in a population-based sample of Queensland families with melanoma. | Aitken J | Journal of the National Cancer Institute | 1999 | PMID: 10070944 |
The p16INK4a/CDKN2A tumor suppressor and its relatives. | Ruas M | Biochimica et biophysica acta | 1998 | PMID: 9823374 |
Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. | Flores JF | Oncogene | 1997 | PMID: 9416844 |
CDKN2A (p16INK4A) somatic and germline mutations. | Smith-Sørensen B | Human mutation | 1996 | PMID: 8723678 |
Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. | Walker GJ | Human molecular genetics | 1995 | PMID: 8595405 |
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Text-mined citations for rs878853650 ...
HelpRecord last updated Jun 23, 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.