ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.379G>T (p.Ala127Ser)
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.379G>T (p.Ala127Ser)
Variation ID: 41578 Accession: VCV000041578.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21970980 (GRCh38) [ NCBI UCSC ] 9: 21970979 (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 12, 2013 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.379G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Ala127Ser missense NM_058195.4:c.*23G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_001195132.2:c.379G>T NP_001182061.1:p.Ala127Ser missense NM_001363763.2:c.226G>T NP_001350692.1:p.Ala76Ser missense NM_058197.5:c.*302G>T 3 prime UTR NC_000009.12:g.21970980C>A NC_000009.11:g.21970979C>A NG_007485.1:g.28512G>T LRG_11:g.28512G>T LRG_11t1:c.379G>T LRG_11p1:p.Ala127Ser P42771:p.Ala127Ser - Protein change
- A127S, A76S
- Other names
- p.A127S:GCA>TCA
- Canonical SPDI
- NC_000009.12:21970979:C: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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0.00739 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00527
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00546
Trans-Omics for Precision Medicine (TOPMed) 0.00611
1000 Genomes Project 0.00739
1000 Genomes Project 30x 0.00796
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
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 |
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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Benign (4) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2023 | RCV000034480.12 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000120541.20 | |
Benign (4) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2020 | RCV000129667.11 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000411295.5 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001081463.9 | |
Likely benign (1) |
criteria provided, single submitter
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May 15, 2022 | RCV002490457.2 |
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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Benign
(Oct 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002072287.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(May 15, 2022)
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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: SCV002802992.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Aug 15, 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: SCV000888056.4
First in ClinVar: Feb 24, 2015 Last updated: Jan 06, 2024 |
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Benign
(Sep 22, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563022.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
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Benign
(Dec 26, 2014)
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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: SCV000184465.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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Benign
(May 01, 2017)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000805828.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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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: SCV001137758.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Benign
(Mar 23, 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: SCV000684527.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Benign
(Jul 12, 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: SCV000488686.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Benign
(Feb 01, 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: SCV000262039.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 12, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000859973.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Dec 06, 2018)
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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: SCV000167652.11
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Comment:
This variant is associated with the following publications: (PMID: 26650189, 28944238, 18983535, 25780468, 7970734, 26104880, 22703879, 22995991, 25064638, 15860862, 20981092, 24728327, 9823374, 19141585, 26775776, 7777061, … (more)
This variant is associated with the following publications: (PMID: 26650189, 28944238, 18983535, 25780468, 7970734, 26104880, 22703879, 22995991, 25064638, 15860862, 20981092, 24728327, 9823374, 19141585, 26775776, 7777061, 10498896, 21462282, 12485439, 29552713, 20505745, 18573309) (less)
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Benign
(Mar 26, 2020)
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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: SCV002534336.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Aug 15, 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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760441.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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no known pathogenicity
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043251.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Benign.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Benign
(Oct 10, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000787995.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000084694.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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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The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
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 |
Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. | Xu H | Nature communications | 2015 | PMID: 26104880 |
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 |
Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. | Potrony M | Journal of the American Academy of Dermatology | 2014 | PMID: 25064638 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Classifying variants of CDKN2A using computational and laboratory studies. | Miller PJ | Human mutation | 2011 | PMID: 21462282 |
Alterations in the p53 pathway and p16INK4a expression predict overall survival in metastatic melanoma patients treated with dacarbazine. | Busch C | The Journal of investigative dermatology | 2010 | PMID: 20505745 |
Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. | Agarwal SK | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19141585 |
CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma. | Pastorino L | Pigment cell & melanoma research | 2008 | PMID: 18983535 |
In silico analysis of structural and functional consequences in p16INK4A by deleterious nsSNPs associated CDKN2A gene in malignant melanoma. | Rajasekaran R | Biochimie | 2008 | PMID: 18573309 |
Role of the CDKN2A locus in patients with multiple primary melanomas. | Puig S | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 15860862 |
Germline and somatic mutations of the INK4a-ARF gene in a xeroderma pigmentosum group C patient. | Soufir N | The Journal of investigative dermatology | 2002 | PMID: 12485439 |
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 |
Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information. | Ruas M | Oncogene | 1999 | PMID: 10498896 |
The p16INK4a/CDKN2A tumor suppressor and its relatives. | Ruas M | Biochimica et biophysica acta | 1998 | PMID: 9823374 |
Intragenic mutations of CDKN2B and CDKN2A in primary human esophageal cancers. | Suzuki H | Human molecular genetics | 1995 | PMID: 8595411 |
Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. | Koh J | Nature | 1995 | PMID: 7777061 |
Mutations and altered expression of p16INK4 in human cancer. | Okamoto A | Proceedings of the National Academy of Sciences of the United States of America | 1994 | PMID: 7972006 |
The MTS1 gene is frequently mutated in primary human esophageal tumors. | Zhou X | Oncogene | 1994 | PMID: 7970734 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CDKN2A | - | - | - | - |
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Text-mined citations for rs6413464 ...
HelpRecord last updated May 08, 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.