ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.170C>T (p.Ala57Val)
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.
Uncertain significance(7); Benign(2); Likely benign(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.170C>T (p.Ala57Val)
Variation ID: 220562 Accession: VCV000220562.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21971189 (GRCh38) [ NCBI UCSC ] 9: 21971188 (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 Sep 28, 2017 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.170C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Ala57Val missense NM_058195.4:c.213C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478102.2:p.Arg71= synonymous NM_001195132.1:c.170C>T NM_001195132.2:c.170C>T NP_001182061.1:p.Ala57Val missense NM_001363763.2:c.17C>T NP_001350692.1:p.Ala6Val missense NM_058197.5:c.*93C>T 3 prime UTR NC_000009.12:g.21971189G>A NC_000009.11:g.21971188G>A NG_007485.1:g.28303C>T LRG_11:g.28303C>T LRG_11t1:c.170C>T LRG_11p1:p.Ala57Val P42771:p.Ala57Val - Protein change
- A57V, A6V
- Other names
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- Canonical SPDI
- NC_000009.12:21971188:G: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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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 |
1236 | 1387 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 9, 2022 | RCV000215562.18 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Apr 17, 2023 | RCV000587917.23 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 13, 2023 | RCV000988157.10 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001079843.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 26, 2023 | RCV003317152.8 |
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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Uncertain significance
(Jan 13, 2017)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000805822.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Benign
(Jul 20, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000910726.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001137774.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 17, 2023)
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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: SCV000292536.14
First in ClinVar: Jul 24, 2016 Last updated: May 06, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with melanoma and/or pancreatic cancer (Soufir 1998, Soufir 2004, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with melanoma and/or pancreatic cancer (Soufir 1998, Soufir 2004, Begg 2005, Orlow 2007, Kannengiesser 2009, Spica 2011); Published functional demonstrate normal or partial binding to CDK4 and elevated levels of reactive oxygen species (Kannengiesser et al., 2009; Jenkins et al., 2013; Li et al., 2022); This variant is associated with the following publications: (PMID: 12752119, 14735200, 21507037, 20707869, 21462282, 9425228, 19260062, 23190892, 9823374, 25980754, 26104880, 16234564, 17218939, 18335566, 18023021, 10596908, 18573309, 19375815, 9132280, 24728327, 21085193, 28440912, 28188106, 27882345, 26664139, 18509008, 16354195, 16896043, 26286987, 28135145, 15146471, 25186627, 29958927, 29769011, 33076392, 35001868, 34369425, 35029067, 18178632) (less)
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Uncertain significance
(Jun 26, 2023)
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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: SCV000695335.2
First in ClinVar: Mar 17, 2018 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CDKN2A c.170C>T (p.Ala57Val) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four … (more)
Variant summary: CDKN2A c.170C>T (p.Ala57Val) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 242428 control chromosomes (gnomAD, Bodian_2014, Goldstein_2008, Xu_2015). This frequency is not significantly higher than estimated for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma (9.5e-05 vs 0.0003), allowing no conclusion about variant significance. c.170C>T has been identified in multiple melanoma patients (e.g. Begg_2005, Goldstein_2008, Kannengiesser_2009, Orlow_2007, Soufir_1998, Soufir_2004), one of whom also had pancreatic cancer (Soufir_2004), as well as in one acute lymphoblastic leukaemia patient (Xu_2015), and in one pancreatic cancer patient without melanoma (Zhu_2021). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Experimental studies have shown that this missense change can partially bind CDK4, resulting in elevated levels of reactive oxygen species, while retaining the cell cycle arrest function (Jenkins 2013, Kannengiesser 2009). The clinical significance of elevated levels of reactive oxygen species (ROS) compared to wild-type p16 is unknown. A subsequent study which applied a computational methodology combining functional data from a cell cycle assay, as well as epidemiological and prediction data, classified this variant as having uncertain significance (Miller 2011). The variant was also shown to effectively suppress leukemic transformation in p16Ink4a deficient mouse cells, to similar levels seen with wild-type (Li_2022). Together, these results show no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 16234564, 24728327, 27756164, 27960642, 28765326, 18178632, 23190892, 19260062, 9166859, 34369425, 21462282, 16818274, 18519632, 17218939, 7718873, 14735200, 9425228, 26104880, 33939675). Nine ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Sep 09, 2022)
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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: SCV000601019.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in affected individuals with melanoma and colorectal cancer (PMIDs: 9425228 (1998), 16234564 (2005), 18178632 (2008), 21462282 … (more)
In the published literature, the variant has been reported in affected individuals with melanoma and colorectal cancer (PMIDs: 9425228 (1998), 16234564 (2005), 18178632 (2008), 21462282 (2011), and 28135145 (2017)). Functional studies have shown that this variant causes partial loss of CDK4 binding, elevated levels of reactive oxygen species, but had a mild effect on cell proliferation and cell cycle regulation (PMIDs: 19260062 (2009) and 23190892 (2013)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(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: SCV000261199.10
First in ClinVar: Feb 02, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(May 02, 2018)
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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: SCV000274603.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Mar 09, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534313.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CDKN2A c.170C>T (p.A57V) variant has been reported in heterozygosity in multiple individuals with melanoma, including at least one patient also affected with pancreatic cancer … (more)
The CDKN2A c.170C>T (p.A57V) variant has been reported in heterozygosity in multiple individuals with melanoma, including at least one patient also affected with pancreatic cancer (PMID: 14735200, 17218939, 18178632); however, it has also been reported in control individuals (PMID: 18178632). In one family with a proband diagnosed with melanoma, this variant did not segregate in an affected family member (PMID: 19260062). The variant has also been reported in an individual with colorectal cancer (PMID: 28135145). In vitro functional studies have demonstrated normal cell cycle regulation, cell proliferation, and/or CDK4 binding (PMID: 21462282, 23190892, 19260062). Functional studies have shown that this variant impaired oxidative regulatory function (PMID: 23190892). In silico predictions of the variant's effect on protein function are inconclusive. This variant was observed in 21/251530 chromosomes across all populations of the large and broad cohorts in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 220562). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010648.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Nov 13, 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:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171402.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The CDKN2A c.170C>T (p.Ala57Val) missense change has a maximum founder subpopulation frequency of 0.013% and a maximum non-founder subpopulation frequency of 0.012% in gnomAD v2.1.1 … (more)
The CDKN2A c.170C>T (p.Ala57Val) missense change has a maximum founder subpopulation frequency of 0.013% and a maximum non-founder subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in an individual with pancreatic cancer and melanoma (PMID: 14735200). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as 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 |
The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia. | Li C | Pharmacogenetics and genomics | 2022 | PMID: 34369425 |
Genetic Variants in Patients With a Family History of Pancreatic Cancer: Impact of Multigene Panel Testing. | Zhu H | Pancreas | 2021 | PMID: 33939675 |
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 |
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 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Familial melanoma-associated mutations in p16 uncouple its tumor-suppressor functions. | Jenkins NC | The Journal of investigative dermatology | 2013 | PMID: 23190892 |
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 |
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 |
CDKN2A mutations and melanoma risk in the Icelandic population. | Goldstein AM | Journal of medical genetics | 2008 | PMID: 18178632 |
CDKN2A germline mutations in individuals with cutaneous malignant melanoma. | Orlow I | The Journal of investigative dermatology | 2007 | PMID: 17218939 |
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 |
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 |
Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma. | Soufir N | British journal of cancer | 2004 | PMID: 14735200 |
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 rs372266620 ...
HelpRecord last updated Jun 02, 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.