ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.369T>A (p.His123Gln)
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(2); Benign(5); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000077.5(CDKN2A):c.369T>A (p.His123Gln)
Variation ID: 127526 Accession: VCV000127526.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21970990 (GRCh38) [ NCBI UCSC ] 9: 21970989 (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 May 27, 2015 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000077.5:c.369T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.His123Gln missense NM_058195.4:c.*13T>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_001195132.2:c.369T>A NP_001182061.1:p.His123Gln missense NM_001363763.2:c.216T>A NP_001350692.1:p.His72Gln missense NM_058197.5:c.*292T>A 3 prime UTR NC_000009.12:g.21970990A>T NC_000009.11:g.21970989A>T NG_007485.1:g.28502T>A LRG_11:g.28502T>A LRG_11t1:c.369T>A LRG_11p1:p.His123Gln P42771:p.His123Gln - Protein change
- H123Q, H72Q
- Other names
- p.H123Q:CAT>CAA
- Canonical SPDI
- NC_000009.12:21970989:A:T
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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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0.00220 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00115
Trans-Omics for Precision Medicine (TOPMed) 0.00128
1000 Genomes Project 0.00220
1000 Genomes Project 30x 0.00344
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2021 | RCV000115336.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 15, 2023 | RCV000254655.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Sep 14, 2023 | RCV000411383.10 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 17, 2023 | RCV000588888.16 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001080834.9 |
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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Likely benign
(Mar 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805826.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
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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: SCV000910615.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Benign
(Jan 08, 2021)
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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: SCV002534333.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Aug 17, 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: SCV004562065.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
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Likely 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: SCV001137760.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Sep 04, 2021)
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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: SCV000695344.3
First in ClinVar: Mar 17, 2018 Last updated: Oct 30, 2021 |
Comment:
Variant summary: CDKN2A c.369T>A (p.His123Gln) 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.369T>A (p.His123Gln) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 243602 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.369T>A has been reported in the literature in individuals affected with Noonan syndrome/glioneuronal tumors, rectal cancer, and one individual who met health insurance criteria for BRCA1/2 or Lynch syndrome gene testing without a specific phenotype being provided (example, Lin_2016, DeRycke_2017, Yorczyk_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. Co-occurrences with other pathogenic variant(s) have been observed at our laboratory and in the literature (our laboratory, BRCA1 c.2679_2682delGAAA, p.Lys893fsX106; Lin_2016, PTPN11 c.923A>G, p.Asn308Ser), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as evidenced by similar cell proliferation and viability levels as wild-type CDKN2A (Kwong-Shing Ng_2018). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a likely benign/benign outcome. Based on the evidence outlined above, the variant was classified as benign. (less)
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Uncertain significance
(Oct 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: SCV000489539.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Sep 21, 2020)
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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: SCV000149245.11
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27978560, 25318351, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27978560, 25318351, 22885699, 27626068, 18573309, 26601054, 16508961, 26366474, 26342236, 28944238, 26206375, 25186627, 9660926, 9823374, 7882348) (less)
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Likely benign
(Sep 14, 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: SCV004018564.3
First in ClinVar: Jul 29, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease … (more)
This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
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Likely benign
(Nov 01, 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: SCV000601029.4
First in ClinVar: Oct 26, 2016 Last updated: Jan 06, 2024 |
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Benign
(Jan 31, 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: SCV000218934.12
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
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Benign
(Sep 29, 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: SCV000216974.7
First in ClinVar: Mar 24, 2015 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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Uncertain significance
(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: SCV004027436.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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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 a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco. | Laraqui A | Journal of genomics | 2021 | PMID: 34646395 |
Systematic Functional Annotation of Somatic Mutations in Cancer. | Ng PK | Cancer cell | 2018 | PMID: 29533785 |
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
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 |
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
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 |
Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle. | Lin FY | Cold Spring Harbor molecular case studies | 2016 | PMID: 27626068 |
Experience with targeted next generation sequencing for the care of lung cancer: insights into promises and limitations of genomic oncology in day-to-day practice. | Rangachari D | Cancer treatment communications | 2015 | PMID: 26601054 |
GESPA: classifying nsSNPs to predict disease association. | Khurana JK | BMC bioinformatics | 2015 | PMID: 26206375 |
Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
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 |
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 |
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 |
The p16INK4a/CDKN2A tumor suppressor and its relatives. | Ruas M | Biochimica et biophysica acta | 1998 | PMID: 9823374 |
Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. | Byeon IJ | Molecular cell | 1998 | PMID: 9660926 |
Loss of heterozygosity on chromosome 9 and p16 (MTS1, CDKN2) gene mutations in esophageal cancers. | Muzeau F | International journal of cancer | 1997 | PMID: 9212218 |
Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. | Kees UR | Blood | 1997 | PMID: 9166859 |
Involvement of CDKN2 (p16INK4A/MTS1) and p15INK4B/MTS2 in human leukemias and lymphomas. | Otsuki T | Cancer research | 1995 | PMID: 7882348 |
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 rs6413463 ...
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.