ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.206A>G (p.Glu69Gly)
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.
Likely pathogenic(1); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000077.5(CDKN2A):c.206A>G (p.Glu69Gly)
Variation ID: 186615 Accession: VCV000186615.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21971153 (GRCh38) [ NCBI UCSC ] 9: 21971152 (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 Dec 19, 2017 Sep 16, 2024 Jul 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.206A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Glu69Gly missense NM_058195.4:c.249A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478102.2:p.Gly83= synonymous NM_001195132.2:c.206A>G NP_001182061.1:p.Glu69Gly missense NM_001363763.2:c.53A>G NP_001350692.1:p.Glu18Gly missense NM_058197.5:c.*129A>G 3 prime UTR NC_000009.12:g.21971153T>C NC_000009.11:g.21971152T>C NG_007485.1:g.28339A>G LRG_11:g.28339A>G LRG_11t1:c.206A>G LRG_11p1:p.Glu69Gly P42771:p.Glu69Gly - Protein change
- E69G, E18G
- Other names
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- Canonical SPDI
- NC_000009.12:21971152:T:C
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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 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00001
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
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 |
1258 | 1410 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 22, 2023 | RCV000166237.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000205699.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 12, 2024 | RCV000235616.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 27, 2024 | RCV003474875.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 22, 2024 | RCV004562366.2 |
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
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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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Likely pathogenic
(Nov 22, 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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Ambry Genetics
Accession: SCV000217017.9
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.E69G variant (also known as c.206A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide … (more)
The p.E69G variant (also known as c.206A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 206 of the p16 protein-encoding isoform. The glutamic acid at codon 69 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in multiple individuals diagnosed with melanoma; however, it did not segregate completely with disease (Goldstein AM et al. Cancer Res. 2006 Oct; 66(20):9818-28; Harland M et al. Hered Cancer Clin Pract 2014;12(1):20; Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; Hatvani Z et al. Exp. Dermatol. 2014 May;23(5):361-4; Cust AE et al. J. Med. Genet., 2011 Apr;48:266-72; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11; Chaudru V et al. Fam. Cancer, 2009 May;8:371-7). This variant showed increased growth as well as decreased binding to both CDK6 and CDK4, although the CDK4 binding defect may be intermediate with respect to other known pathogenic CDKN2A missense mutations (Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). Another functional study reported this variant as neutral based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 01;11:). Based on internal structural analysis, this amino acid lies within the probable CDK4 binding site and is in close contact with other amino acids at which other pathogenic missense substitutions are found; however the change from glutamic acid to glycine is predicted to only mildly destabilize local structure and protein-protein binding interactions (Ambry internal data; Kannengiesser C et al. Hum. Mutat. 2009 Apr; 30(4):564-74; Russo AA et al. Nature, 1998 Sep;395:237-43). Based on the majority of available evidence to date, this variant is likely to be pathogenic with moderate risk. (less)
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Uncertain significance
(Mar 27, 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: SCV004212463.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Jul 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917150.5
First in ClinVar: Jun 02, 2019 Last updated: Sep 16, 2024 |
Comment:
Variant summary: CDKN2A c.206A>G (p.Glu69Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: CDKN2A c.206A>G (p.Glu69Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 1593674 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma (4.2e-05 vs 0.0003), allowing no conclusion about variant significance. The variant, c.206A>G, has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Chandru_2009, Cust_2011, Goldstein_2006, Hatvani_2014, Miller_2011). The variant has been found to lack co-segregation with disease being observed in unaffected individuals, along with being absent from affected individuals (Kannengiesser_2009, Miller_2011). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrence with another pathogenic variant has been reported (MLH1 c.589-2A>G) (Yurgelun_2015), providing supporting evidence for a benign role. Functional studies report the variant affects CDK4 and CDK6 binding ability, Ki67 index and cellular locatization of p16 protein (McKenzie_2010, Kannengiesser_2009). The following publications have been ascertained in the context of this evaluation (PMID: 21462282, 25980754, 25780468, 20340136, 21325014, 17047042, 26104880, 19260062, 28135145, 19484507, 24660985, 30303537, 30709382, 35001868). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 21, 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: SCV000902849.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with glycine at codon 69 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with glycine at codon 69 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to exhibit reduced binding to CDK4 and/or CDK6 (PMID: 19260062, 20340136); however, cell proliferation and cell cycle progression assays showed activity comparable to wild-type (PMID: 35001868). This variant has been reported in individuals affected with melanoma (PMID: 17047042, 19484507, 21325014, 21462282, 24660985, 25780468), colorectal cancer (PMID: 25980754, 28135145), and breast cancer (PMID: 33753322). However, the variant did not show segregation with melanoma in multiple families; the variant was observed in unaffected individuals (PMID: 21462282) and was absent in some affected individuals (PMID: 19260062). This variant has been observed together with pathogenic BRCA2 variants in two unrelated families and with a pathogenic CHEK2 variant in a family with a history of melanoma and prostate cancer (Color internal data). This variant has been identified in 2/211552 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 29, 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: SCV000262212.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 69 of the CDKN2A (p16INK4a) … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 69 of the CDKN2A (p16INK4a) protein (p.Glu69Gly). This variant is present in population databases (rs372670098, gnomAD 0.002%). This missense change has been observed in individual(s) with melanoma (PMID: 17047042, 21325014, 24660985). ClinVar contains an entry for this variant (Variation ID: 186615). 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 tolerated. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 19260062, 20340136). 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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Uncertain significance
(Jul 12, 2024)
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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: SCV000292537.13
First in ClinVar: Jul 24, 2016 Last updated: Sep 16, 2024 |
Comment:
Published functional studies are inconclusive: reduced CDK4 and CDK6 binding ability but no effect on cell proliferation (PMID: 19260062, 20340136, 35001868); Observed in individuals and … (more)
Published functional studies are inconclusive: reduced CDK4 and CDK6 binding ability but no effect on cell proliferation (PMID: 19260062, 20340136, 35001868); Observed in individuals and families with CDKN2A-related cancers (PMID: 17047042, 16905682, 19260062, 25780468, 24660985); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25780468, 17047042, 21325014, 26104880, 9425228, 25980754, 20340136, 19260062, 24660985, 21462282, 20876876, 16905682, 19484507, 28135145, 30709382, 35001868, 33753322, 29922827) (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 |
Incidental findings in a series of 2500 gene panel tests for a genetic predisposition to cancer: Results and impact on patients. | Nambot S | European journal of medical genetics | 2021 | PMID: 33753322 |
Analysis on GENIE reveals novel recurrent variants that affect molecular diagnosis of sizable number of cancer patients. | Koyama T | BMC cancer | 2019 | PMID: 30709382 |
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature. | Craddock CF | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28765326 |
Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI. | Carraro M | Human mutation | 2017 | PMID: 28440912 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Biallelic loss of CDKN2A is associated with poor response to treatment in pediatric acute lymphoblastic leukemia. | Braun M | Leukemia & lymphoma | 2017 | PMID: 27756164 |
The role of CDKN2A/B deletions in pediatric acute lymphoblastic leukemia. | Carrasco Salas P | Pediatric hematology and oncology | 2016 | PMID: 27960642 |
Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. | Xu H | Nature communications | 2015 | PMID: 26104880 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
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 |
Genotype analysis in Hungarian patients with multiple primary melanoma. | Hatvani Z | Experimental dermatology | 2014 | PMID: 24660985 |
Classifying variants of CDKN2A using computational and laboratory studies. | Miller PJ | Human mutation | 2011 | PMID: 21462282 |
Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. | Cust AE | Journal of medical genetics | 2011 | PMID: 21325014 |
Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. | McKenzie HA | Human mutation | 2010 | PMID: 20340136 |
Protective effect of copy number polymorphism of glutathione S-transferase T1 gene on melanoma risk in presence of CDKN2A mutations, MC1R variants and host-related phenotypes. | Chaudru V | Familial cancer | 2009 | PMID: 19484507 |
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 |
Failure of CDKN2A/B (INK4A/B-ARF)-mediated tumor suppression and resistance to targeted therapy in acute lymphoblastic leukemia induced by BCR-ABL. | Mullighan CG | Genes & development | 2008 | PMID: 18519632 |
High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. | Goldstein AM | Cancer research | 2006 | PMID: 17047042 |
The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. | Mirebeau D | Haematologica | 2006 | PMID: 16818274 |
Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. | Russo AA | Nature | 1998 | PMID: 9751050 |
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 |
Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. | Kees UR | Blood | 1997 | PMID: 9166859 |
Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. | Sill H | Blood | 1995 | PMID: 7718873 |
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Text-mined citations for rs372670098 ...
HelpRecord last updated Sep 17, 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.