ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.301G>T (p.Gly101Trp)
Germline
Classification
Help
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.
(22)
Help
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.
Pathogenic
22
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000077.5(CDKN2A):c.301G>T (p.Gly101Trp)
Variation ID: 9412 Accession: VCV000009412.71
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p21.3 9: 21971058 (GRCh38) [ NCBI UCSC ] 9: 21971057 (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 4, 2013 Oct 20, 2024 Jul 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000077.5:c.301G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Gly101Trp missense NM_058195.4:c.344G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478102.2:p.Arg115Leu missense NM_001195132.2:c.301G>T NP_001182061.1:p.Gly101Trp missense NM_001363763.2:c.148G>T NP_001350692.1:p.Gly50Trp missense NM_058197.5:c.*224G>T 3 prime UTR NC_000009.12:g.21971058C>A NC_000009.11:g.21971057C>A NG_007485.1:g.28434G>T LRG_11:g.28434G>T LRG_11t1:c.301G>T LRG_11p1:p.Gly101Trp LRG_11t2:c.344G>T LRG_11p2:p.Arg115Leu P42771:p.Gly101Trp - Protein change
- G101W, R115L, G50W
- Other names
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p.G101W:GGG>TGG
- Canonical SPDI
- NC_000009.12:21971057: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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 |
1261 | 1413 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 4, 2022 | RCV000010018.7 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 20, 2023 | RCV000010019.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000196633.17 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2015 | RCV000415140.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 27, 2023 | RCV000115334.20 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV000212400.43 | |
| Pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2024 | RCV003473075.2 | |
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CDKN2A-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jul 18, 2024 | RCV004754252.1 |
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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Pathogenic
(Jun 18, 2015)
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criteria provided, single submitter
Method: clinical testing
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Malignant melanoma of skin
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492851.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Jan 17, 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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Eurofins Ntd Llc (ga)
Accession: SCV000705284.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Melanoma-pancreatic cancer syndrome
Affected status: yes
Allele origin:
germline
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000897974.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
Age: 40-49 years
Sex: male
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Pathogenic
(Jul 17, 2017)
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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: SCV000601024.2
First in ClinVar: Mar 08, 2017 Last updated: May 09, 2020 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. … (more)
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families. (less)
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Pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762158.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Soft tissue sarcoma (present)
Sex: male
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518658.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(May 12, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547810.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: CDKN2A c.301G>T (p.Gly101Trp) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Five of … (more)
Variant summary: CDKN2A c.301G>T (p.Gly101Trp) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234668 control chromosomes (gnomAD, Kamb_1994). c.301G>T has been reported in the literature in multiple individuals affected with Melanoma (e.g. Kamb_1994, Hussussian_1994, Blackwood_2002). These data indicate that the variant is very likely to be associated with disease. . Kannengiesser_2008 reports that the variant causes a loss of CDK4 binding which results in aberrant proliferation in cell culture. This was was confirmed by Miller_2011, who showed that in a cell cycle arrest assay, the variant caused a complete loss of cell cycle arrest. Twelve ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 20, 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: SCV004018548.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11556834, 17047042].
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Pathogenic
(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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253762.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been … (more)
The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the CDKN2A (p16INK4a) protein (p.Gly101Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 10869234, 11807902, 14679123, 15146471, 21462282, 21801156). It has also been observed to segregate with disease in related individuals. This variant is also known as c.344G>T (p.Arg115Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9412). 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 disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20340136, 21462282). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. (less)
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Pathogenic
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550362.6
First in ClinVar: Jul 27, 2022 Last updated: Aug 04, 2024 |
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Pathogenic
(May 27, 2022)
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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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196963.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Melanoma-pancreatic cancer syndrome
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499646.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Aug 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579411.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PS3_MOD, PM1_SUP, PM2_SUP, PP3, PP4
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Feb 01, 2017)
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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: SCV000677725.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Feb 27, 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: SCV000684520.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces glycine with tryptophan at codon 101 in the … (more)
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces glycine with tryptophan at codon 101 in the ankyrin repeat motif of the CDKN2A (p16INK4A) protein. This variant is also known as p.Gly93Trp in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs the ability of p16INK4A protein to bind CDK4 and CDK6 and control cell cycle (PMID: 7566978, 7647780, 9324288, 19260062, 20340136, 21462282, 24659262). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 9425228, 11579459, 12072543, 14679123, 15146471, 15860862, 16234564, 19360740, 20340136, 21801156, 22841127, 25780468, 26381259, 26658419, 26681309, 26775776, 27181379, 28146043, 29464027, 29945567, 30274933, 31432501, 31517177, 32455486). This variant has been shown to segregate with disease in many families (PMID: 7666917, 7987387, 8552158, 9425228, 10508477) and is thought to be a European founder mutation (PMID: 10869234, 11579459, 15860862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 07, 2021)
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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: SCV000184621.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.G101W pathogenic mutation (also known as c.301G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at … (more)
The p.G101W pathogenic mutation (also known as c.301G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 301. The glycine at codon 101 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous individuals diagnosed with FAMMM (Whelan AJ et al. N. Engl. J. Med. 1995 Oct;333:975-7; Ranade K et al. Nat. Genet.,1995 May;10:114-6; Gironi LC et al. Int. J. Dermatol. 2015 Dec;54:e553-5; Roberts NJ et al. Cancer Discov. 2016 Feb;6:166-75). It has also been reported as one of the most common CDKN2A mutations (Vinarsky V et al. Head Neck. 2009;31:1524-7; Puig S et al. Genet Med, 2016 07;18:727-36). In one meta-analysis, 9 of 22 families with this mutation reported at least one case of pancreatic cancer (Goldstein AM et al. Hum. Mutat. 2004; 23:630). Several functional studies have revealed a significant decrease in the ability of p.G101W to inhibit cell growth (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Miller PJ et al. Hum. Mutat. 2011;32:900-11). In addition, while some studies have shown that the mutant protein maintains some ability to bind with CDK4, additional studies have demonstrated that the binding affinity is temperature dependent, with 75% of binding affinity compared to wildtype at 30 degrees Celsius, but <10% of binding affinity compared to wildtype at 42 degrees Celsius (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Kannengiesser C et al. Hum. Mutat. 2009;30:564-74; Parry D et al. Mol. Cell. Biol. 1996 Jul;16(7):3844-52). Further, mass spectrometry analysis of this alteration indicates a significantly altered structure, and in silico molecular dynamics simulations predict that this alteration creates a misfolding of the third and fourth ankryin repeats, with a partial conservation of the first and second repeats at the binding site, which explains its partial retention of CDK4 binding in vitro but its inability to block cell proliferation (Tevelev A et al. Biochemistry. 1996 Jul;35(29):9475-87; Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). The partially folded state is predicted to promote faster degradation, resulting in a decreased half-life of the protein and a higher tendency to form protein aggregates (Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). Of note, this pathogenic mutation has also been reported in the literature as p.G93W (c.295G>T). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 28, 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: SCV004212514.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(May 28, 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: SCV000149243.15
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Reported in association with familial melanoma and pancreatic cancer, and is a common pathogenic founder variant observed to segregate with disease in numerous geographically-diverse families … (more)
Reported in association with familial melanoma and pancreatic cancer, and is a common pathogenic founder variant observed to segregate with disease in numerous geographically-diverse families (PMID: 7987387, 7666917, 10869234, 11807902, 14679123, 19500876, 26775776, 26681309); Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition and CDK4 and CDK6 binding (PMID: 7647780, 7780957, 8668202, 9324288, 19260062, 20340136, 21462282, 24659262); This variant in the p16 isoform also results in a variant of uncertain significance in the p14-ARF protein, c.344G>T (p.Arg115Leu); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22804906, 19158841, 26225579, 27181379, 25787093, 22841127, 26650572, 25970827, 36980738, 35988656, 36717525, 32191290, 36495689, 28146043, 28452926, 28726808, 7780957, 7777061, 8668202, 9324288, 10389768, 19260062, 20340136, 21462282, 18024887, 10869234, 17167857, 25780468, 15235029, 15140239, 10874641, 25803691, 7987388, 19500876, 7566978, 14679123, 7647780, 24659262, 7987387, 19360740, 15860862, 11807902, 26681309, 22368299, 25023876, 25431349, 26775776, 26800492, 26892652, 26650189, 27473757, 26658419, 28060055, 26381259, 28030792, 28592523, 27926368, 29464027, 20653773, 7666917, 29543703, 30113427, 30338612, 31432501, 11243640, 36139606, 12001124, 27960642, 21801156, 8012957, 16818274, 27756164, 9166859, 9425228, 15146471, 11579459, 8552158, 7718873, 29922827, 32482799, 18519632, 35123577, 31628766, 30218143, 30291219, 28765326) (less)
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Pathogenic
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246066.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Comment:
CDKN2A: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting, BP4
Number of individuals with the variant: 4
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risk factor
(Jun 01, 2010)
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no assertion criteria provided
Method: literature only
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MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030239.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 families with melanoma (155601), Hussussian et al. (1994) identified a gly93-to-trp mutation in the CDKN2A gene. (The GLY93TRP mutation is now designated GLY101TRP.) … (more)
In 3 families with melanoma (155601), Hussussian et al. (1994) identified a gly93-to-trp mutation in the CDKN2A gene. (The GLY93TRP mutation is now designated GLY101TRP.) Whelan et al. (1995) described a kindred with an increased risk of pancreatic cancers, melanomas, and possibly additional types of tumors (see 606719) cosegregating with the gly93-to-trp CDKN2 mutation. Of interest was the occurrence of squamous-cell carcinomas in this family, a rare form, and squamous cell carcinoma of the tongue in the proband. More than half of primary esophageal squamous cell carcinomas have CDKN2 mutations (Mori et al., 1994). The mutation was identified by SSCP analysis and was located in exon 2 where direct sequencing demonstrated a G-to-T nucleotide change at position 295. Ciotti et al. (1996) indicated that in a small geographic area of Italy (possibly because of founder effect), they had detected the gly93-to-trp mutation in 7 apparently unrelated families and in none of 50 control persons. Nineteen cases of melanoma and 3 of dysplastic nevi were diagnosed at ages ranging from 21 to 70 years in the kindreds with the G93W mutation. In addition, 15 cancers at other sites were found in these kindreds, including 3 pancreatic cancers but no gastric cancers. The pancreatic tumors developed in members of 3 different families at the ages of 48, 51, and 60 years. Ciotti et al. (2000) stated that gly101-to-trp is the most common CDKN2A missense mutation, having been reported in numerous families from around the world, with a particularly high occurrence in France and Italy. They examined the date of origin of the mutation and its migratory spread in 10 families from Italy, 4 families from the U.S., and 6 families from France. In all families studied, the mutation appeared to have been derived from a single ancestral haplotype. Using maximum likelihood methods, they estimated that the mutation arose 97 generations ago, providing some explanation for the wide geographic spread of this common mutation, particularly in southwestern Europe. All of the Italian families, with one exception, came from a small area on the eastern coast of Liguria. Auroy et al. (2001) found the G101W mutation in 7 patients with multiple primary melanomas with no known melanoma cases within their families. They stated that the mutation had already been described in more than 20 melanoma-prone families. They genotyped 8 microsatellite markers flanking the CDKN2A gene and found, after allowing for recombination over time, that haplotype sharing provided evidence for an original G101W mutation common to 6 of the 7 sporadic multiple primary melanoma cases. In Italy, Mantelli et al. (2002) screened for CDKN2A mutations in families with 2 melanoma patients, 1 of whom was younger than 50 years at onset and the other complying with 1 of the following: being a first-degree relative; having an additional relative with pancreatic cancer; or having multiple primary melanomas. Mutations were found in 21 of the 62 families (34%) with a high prevalence of the G101W mutation (18 of 21). In in vitro functional studies in mammalian cells, McKenzie et al. (2010) found that the G101W mutant protein had decreased binding to CDK4 (123829) (about 20% of wildtype). Cell cycle inhibitory activity was similar to wildtype at 37 degrees Celsius, but was decreased at 40 degrees. (less)
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Pathogenic
(Jun 01, 2010)
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no assertion criteria provided
Method: literature only
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MELANOMA-PANCREATIC CANCER SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030240.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 families with melanoma (155601), Hussussian et al. (1994) identified a gly93-to-trp mutation in the CDKN2A gene. (The GLY93TRP mutation is now designated GLY101TRP.) … (more)
In 3 families with melanoma (155601), Hussussian et al. (1994) identified a gly93-to-trp mutation in the CDKN2A gene. (The GLY93TRP mutation is now designated GLY101TRP.) Whelan et al. (1995) described a kindred with an increased risk of pancreatic cancers, melanomas, and possibly additional types of tumors (see 606719) cosegregating with the gly93-to-trp CDKN2 mutation. Of interest was the occurrence of squamous-cell carcinomas in this family, a rare form, and squamous cell carcinoma of the tongue in the proband. More than half of primary esophageal squamous cell carcinomas have CDKN2 mutations (Mori et al., 1994). The mutation was identified by SSCP analysis and was located in exon 2 where direct sequencing demonstrated a G-to-T nucleotide change at position 295. Ciotti et al. (1996) indicated that in a small geographic area of Italy (possibly because of founder effect), they had detected the gly93-to-trp mutation in 7 apparently unrelated families and in none of 50 control persons. Nineteen cases of melanoma and 3 of dysplastic nevi were diagnosed at ages ranging from 21 to 70 years in the kindreds with the G93W mutation. In addition, 15 cancers at other sites were found in these kindreds, including 3 pancreatic cancers but no gastric cancers. The pancreatic tumors developed in members of 3 different families at the ages of 48, 51, and 60 years. Ciotti et al. (2000) stated that gly101-to-trp is the most common CDKN2A missense mutation, having been reported in numerous families from around the world, with a particularly high occurrence in France and Italy. They examined the date of origin of the mutation and its migratory spread in 10 families from Italy, 4 families from the U.S., and 6 families from France. In all families studied, the mutation appeared to have been derived from a single ancestral haplotype. Using maximum likelihood methods, they estimated that the mutation arose 97 generations ago, providing some explanation for the wide geographic spread of this common mutation, particularly in southwestern Europe. All of the Italian families, with one exception, came from a small area on the eastern coast of Liguria. Auroy et al. (2001) found the G101W mutation in 7 patients with multiple primary melanomas with no known melanoma cases within their families. They stated that the mutation had already been described in more than 20 melanoma-prone families. They genotyped 8 microsatellite markers flanking the CDKN2A gene and found, after allowing for recombination over time, that haplotype sharing provided evidence for an original G101W mutation common to 6 of the 7 sporadic multiple primary melanoma cases. In Italy, Mantelli et al. (2002) screened for CDKN2A mutations in families with 2 melanoma patients, 1 of whom was younger than 50 years at onset and the other complying with 1 of the following: being a first-degree relative; having an additional relative with pancreatic cancer; or having multiple primary melanomas. Mutations were found in 21 of the 62 families (34%) with a high prevalence of the G101W mutation (18 of 21). In in vitro functional studies in mammalian cells, McKenzie et al. (2010) found that the G101W mutant protein had decreased binding to CDK4 (123829) (about 20% of wildtype). Cell cycle inhibitory activity was similar to wildtype at 37 degrees Celsius, but was decreased at 40 degrees. (less)
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Pathogenic
(Jul 18, 2024)
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no assertion criteria provided
Method: clinical testing
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CDKN2A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005361037.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The CDKN2A c.301G>T variant is predicted to result in the amino acid substitution p.Gly101Trp. This variant has been reported in several individuals to be causative … (more)
The CDKN2A c.301G>T variant is predicted to result in the amino acid substitution p.Gly101Trp. This variant has been reported in several individuals to be causative for melanoma, mesothelioma, and pancreatic cancer (reported as 295 codon 93 Gly to Trp in Hussussian et al. 1994. PubMed ID: 7987387; Betti et al. 2016. PubMed: 27181379; Supplemental table S10, Roberts et al. 2016. PubMed ID: 26658419). In addition, functional studies supports its deleterious effect (Kannengiesser et al. 2009. PubMed ID: 19260062; McKenzie et al. 2010. PubMed ID: 20340136; Miller et al. 2011. PubMed ID: 21462282). This variant has not been reported in a large population database; and, it has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9412/). In summary, this variant is interpreted as pathogenic. (less)
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Citation text
Hussussian, C. J., Struewing, J. P., Goldstein, A. M., Higgins, P. A. T., Ally, D. S., Sheahan, M. D., Clark, W. H., Jr., Tucker, M. A., Dracopoli, N. C. Germline p16 mutations in familial melanoma. Nature Genet. 8: 15-21, 1994.
Citation text
Hussussian, C. J., Struewing, J. P., Goldstein, A. M., Higgins, P. A. T., Ally, D. S., Sheahan, M. D., Clark, W. H., Jr., Tucker, M. A., Dracopoli, N. C. Germline p16 mutations in familial melanoma. Nature Genet. 8: 15-21, 1994.
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families.
Comment:
Variant summary: CDKN2A c.301G>T (p.Gly101Trp) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234668 control chromosomes (gnomAD, Kamb_1994). c.301G>T has been reported in the literature in multiple individuals affected with Melanoma (e.g. Kamb_1994, Hussussian_1994, Blackwood_2002). These data indicate that the variant is very likely to be associated with disease. . Kannengiesser_2008 reports that the variant causes a loss of CDK4 binding which results in aberrant proliferation in cell culture. This was was confirmed by Miller_2011, who showed that in a cell cycle arrest assay, the variant caused a complete loss of cell cycle arrest. Twelve ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11556834, 17047042].
Comment:
The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the CDKN2A (p16INK4a) protein (p.Gly101Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 10869234, 11807902, 14679123, 15146471, 21462282, 21801156). It has also been observed to segregate with disease in related individuals. This variant is also known as c.344G>T (p.Arg115Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9412). 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 disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20340136, 21462282). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear.
Comment:
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces glycine with tryptophan at codon 101 in the ankyrin repeat motif of the CDKN2A (p16INK4A) protein. This variant is also known as p.Gly93Trp in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs the ability of p16INK4A protein to bind CDK4 and CDK6 and control cell cycle (PMID: 7566978, 7647780, 9324288, 19260062, 20340136, 21462282, 24659262). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 9425228, 11579459, 12072543, 14679123, 15146471, 15860862, 16234564, 19360740, 20340136, 21801156, 22841127, 25780468, 26381259, 26658419, 26681309, 26775776, 27181379, 28146043, 29464027, 29945567, 30274933, 31432501, 31517177, 32455486). This variant has been shown to segregate with disease in many families (PMID: 7666917, 7987387, 8552158, 9425228, 10508477) and is thought to be a European founder mutation (PMID: 10869234, 11579459, 15860862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.G101W pathogenic mutation (also known as c.301G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 301. The glycine at codon 101 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous individuals diagnosed with FAMMM (Whelan AJ et al. N. Engl. J. Med. 1995 Oct;333:975-7; Ranade K et al. Nat. Genet.,1995 May;10:114-6; Gironi LC et al. Int. J. Dermatol. 2015 Dec;54:e553-5; Roberts NJ et al. Cancer Discov. 2016 Feb;6:166-75). It has also been reported as one of the most common CDKN2A mutations (Vinarsky V et al. Head Neck. 2009;31:1524-7; Puig S et al. Genet Med, 2016 07;18:727-36). In one meta-analysis, 9 of 22 families with this mutation reported at least one case of pancreatic cancer (Goldstein AM et al. Hum. Mutat. 2004; 23:630). Several functional studies have revealed a significant decrease in the ability of p.G101W to inhibit cell growth (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Miller PJ et al. Hum. Mutat. 2011;32:900-11). In addition, while some studies have shown that the mutant protein maintains some ability to bind with CDK4, additional studies have demonstrated that the binding affinity is temperature dependent, with 75% of binding affinity compared to wildtype at 30 degrees Celsius, but <10% of binding affinity compared to wildtype at 42 degrees Celsius (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Kannengiesser C et al. Hum. Mutat. 2009;30:564-74; Parry D et al. Mol. Cell. Biol. 1996 Jul;16(7):3844-52). Further, mass spectrometry analysis of this alteration indicates a significantly altered structure, and in silico molecular dynamics simulations predict that this alteration creates a misfolding of the third and fourth ankryin repeats, with a partial conservation of the first and second repeats at the binding site, which explains its partial retention of CDK4 binding in vitro but its inability to block cell proliferation (Tevelev A et al. Biochemistry. 1996 Jul;35(29):9475-87; Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). The partially folded state is predicted to promote faster degradation, resulting in a decreased half-life of the protein and a higher tendency to form protein aggregates (Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). Of note, this pathogenic mutation has also been reported in the literature as p.G93W (c.295G>T). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Reported in association with familial melanoma and pancreatic cancer, and is a common pathogenic founder variant observed to segregate with disease in numerous geographically-diverse families (PMID: 7987387, 7666917, 10869234, 11807902, 14679123, 19500876, 26775776, 26681309); Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition and CDK4 and CDK6 binding (PMID: 7647780, 7780957, 8668202, 9324288, 19260062, 20340136, 21462282, 24659262); This variant in the p16 isoform also results in a variant of uncertain significance in the p14-ARF protein, c.344G>T (p.Arg115Leu); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22804906, 19158841, 26225579, 27181379, 25787093, 22841127, 26650572, 25970827, 36980738, 35988656, 36717525, 32191290, 36495689, 28146043, 28452926, 28726808, 7780957, 7777061, 8668202, 9324288, 10389768, 19260062, 20340136, 21462282, 18024887, 10869234, 17167857, 25780468, 15235029, 15140239, 10874641, 25803691, 7987388, 19500876, 7566978, 14679123, 7647780, 24659262, 7987387, 19360740, 15860862, 11807902, 26681309, 22368299, 25023876, 25431349, 26775776, 26800492, 26892652, 26650189, 27473757, 26658419, 28060055, 26381259, 28030792, 28592523, 27926368, 29464027, 20653773, 7666917, 29543703, 30113427, 30338612, 31432501, 11243640, 36139606, 12001124, 27960642, 21801156, 8012957, 16818274, 27756164, 9166859, 9425228, 15146471, 11579459, 8552158, 7718873, 29922827, 32482799, 18519632, 35123577, 31628766, 30218143, 30291219, 28765326)
Comment:
CDKN2A: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting, BP4
Comment:
The CDKN2A c.301G>T variant is predicted to result in the amino acid substitution p.Gly101Trp. This variant has been reported in several individuals to be causative for melanoma, mesothelioma, and pancreatic cancer (reported as 295 codon 93 Gly to Trp in Hussussian et al. 1994. PubMed ID: 7987387; Betti et al. 2016. PubMed: 27181379; Supplemental table S10, Roberts et al. 2016. PubMed ID: 26658419). In addition, functional studies supports its deleterious effect (Kannengiesser et al. 2009. PubMed ID: 19260062; McKenzie et al. 2010. PubMed ID: 20340136; Miller et al. 2011. PubMed ID: 21462282). This variant has not been reported in a large population database; and, it has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9412/). In summary, this variant is interpreted as pathogenic.
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. |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families.
Comment:
Variant summary: CDKN2A c.301G>T (p.Gly101Trp) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234668 control chromosomes (gnomAD, Kamb_1994). c.301G>T has been reported in the literature in multiple individuals affected with Melanoma (e.g. Kamb_1994, Hussussian_1994, Blackwood_2002). These data indicate that the variant is very likely to be associated with disease. . Kannengiesser_2008 reports that the variant causes a loss of CDK4 binding which results in aberrant proliferation in cell culture. This was was confirmed by Miller_2011, who showed that in a cell cycle arrest assay, the variant caused a complete loss of cell cycle arrest. Twelve ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11556834, 17047042].
Comment:
The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the CDKN2A (p16INK4a) protein (p.Gly101Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 10869234, 11807902, 14679123, 15146471, 21462282, 21801156). It has also been observed to segregate with disease in related individuals. This variant is also known as c.344G>T (p.Arg115Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9412). 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 disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20340136, 21462282). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear.
Comment:
The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces glycine with tryptophan at codon 101 in the ankyrin repeat motif of the CDKN2A (p16INK4A) protein. This variant is also known as p.Gly93Trp in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs the ability of p16INK4A protein to bind CDK4 and CDK6 and control cell cycle (PMID: 7566978, 7647780, 9324288, 19260062, 20340136, 21462282, 24659262). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 9425228, 11579459, 12072543, 14679123, 15146471, 15860862, 16234564, 19360740, 20340136, 21801156, 22841127, 25780468, 26381259, 26658419, 26681309, 26775776, 27181379, 28146043, 29464027, 29945567, 30274933, 31432501, 31517177, 32455486). This variant has been shown to segregate with disease in many families (PMID: 7666917, 7987387, 8552158, 9425228, 10508477) and is thought to be a European founder mutation (PMID: 10869234, 11579459, 15860862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.G101W pathogenic mutation (also known as c.301G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 301. The glycine at codon 101 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous individuals diagnosed with FAMMM (Whelan AJ et al. N. Engl. J. Med. 1995 Oct;333:975-7; Ranade K et al. Nat. Genet.,1995 May;10:114-6; Gironi LC et al. Int. J. Dermatol. 2015 Dec;54:e553-5; Roberts NJ et al. Cancer Discov. 2016 Feb;6:166-75). It has also been reported as one of the most common CDKN2A mutations (Vinarsky V et al. Head Neck. 2009;31:1524-7; Puig S et al. Genet Med, 2016 07;18:727-36). In one meta-analysis, 9 of 22 families with this mutation reported at least one case of pancreatic cancer (Goldstein AM et al. Hum. Mutat. 2004; 23:630). Several functional studies have revealed a significant decrease in the ability of p.G101W to inhibit cell growth (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Miller PJ et al. Hum. Mutat. 2011;32:900-11). In addition, while some studies have shown that the mutant protein maintains some ability to bind with CDK4, additional studies have demonstrated that the binding affinity is temperature dependent, with 75% of binding affinity compared to wildtype at 30 degrees Celsius, but <10% of binding affinity compared to wildtype at 42 degrees Celsius (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Kannengiesser C et al. Hum. Mutat. 2009;30:564-74; Parry D et al. Mol. Cell. Biol. 1996 Jul;16(7):3844-52). Further, mass spectrometry analysis of this alteration indicates a significantly altered structure, and in silico molecular dynamics simulations predict that this alteration creates a misfolding of the third and fourth ankryin repeats, with a partial conservation of the first and second repeats at the binding site, which explains its partial retention of CDK4 binding in vitro but its inability to block cell proliferation (Tevelev A et al. Biochemistry. 1996 Jul;35(29):9475-87; Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). The partially folded state is predicted to promote faster degradation, resulting in a decreased half-life of the protein and a higher tendency to form protein aggregates (Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). Of note, this pathogenic mutation has also been reported in the literature as p.G93W (c.295G>T). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Reported in association with familial melanoma and pancreatic cancer, and is a common pathogenic founder variant observed to segregate with disease in numerous geographically-diverse families (PMID: 7987387, 7666917, 10869234, 11807902, 14679123, 19500876, 26775776, 26681309); Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition and CDK4 and CDK6 binding (PMID: 7647780, 7780957, 8668202, 9324288, 19260062, 20340136, 21462282, 24659262); This variant in the p16 isoform also results in a variant of uncertain significance in the p14-ARF protein, c.344G>T (p.Arg115Leu); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22804906, 19158841, 26225579, 27181379, 25787093, 22841127, 26650572, 25970827, 36980738, 35988656, 36717525, 32191290, 36495689, 28146043, 28452926, 28726808, 7780957, 7777061, 8668202, 9324288, 10389768, 19260062, 20340136, 21462282, 18024887, 10869234, 17167857, 25780468, 15235029, 15140239, 10874641, 25803691, 7987388, 19500876, 7566978, 14679123, 7647780, 24659262, 7987387, 19360740, 15860862, 11807902, 26681309, 22368299, 25023876, 25431349, 26775776, 26800492, 26892652, 26650189, 27473757, 26658419, 28060055, 26381259, 28030792, 28592523, 27926368, 29464027, 20653773, 7666917, 29543703, 30113427, 30338612, 31432501, 11243640, 36139606, 12001124, 27960642, 21801156, 8012957, 16818274, 27756164, 9166859, 9425228, 15146471, 11579459, 8552158, 7718873, 29922827, 32482799, 18519632, 35123577, 31628766, 30218143, 30291219, 28765326)
Comment:
CDKN2A: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting, BP4
Comment:
The CDKN2A c.301G>T variant is predicted to result in the amino acid substitution p.Gly101Trp. This variant has been reported in several individuals to be causative for melanoma, mesothelioma, and pancreatic cancer (reported as 295 codon 93 Gly to Trp in Hussussian et al. 1994. PubMed ID: 7987387; Betti et al. 2016. PubMed: 27181379; Supplemental table S10, Roberts et al. 2016. PubMed ID: 26658419). In addition, functional studies supports its deleterious effect (Kannengiesser et al. 2009. PubMed ID: 19260062; McKenzie et al. 2010. PubMed ID: 20340136; Miller et al. 2011. PubMed ID: 21462282). This variant has not been reported in a large population database; and, it has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9412/). In summary, this variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Dermoscopy comparative approach for early diagnosis in familial melanoma: influence of MC1R genotype. | Longo C | Journal of the European Academy of Dermatology and Venereology : JEADV | 2021 | PMID: 32455486 |
| Expanded analysis of secondary germline findings from matched tumor/normal sequencing identifies additional clinically significant mutations. | Dumbrava EI | JCO precision oncology | 2019 | PMID: 31517177 |
| Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort. | Schwartz M | Clinical genetics | 2019 | PMID: 31432501 |
| CDKN2A germline mutations are not associated with poor survival in an Italian cohort of melanoma patients. | Dalmasso B | Journal of the American Academy of Dermatology | 2019 | PMID: 30274933 |
| Pancreatic cancer as a sentinel for hereditary cancer predisposition. | Young EL | BMC cancer | 2018 | PMID: 29945567 |
| Combining molecular and immunohistochemical analyses of key drivers in primary melanomas: interplay between germline and somatic variations. | Bruno W | Oncotarget | 2017 | PMID: 29464027 |
| 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 |
| Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. | Jouenne F | Journal of medical genetics | 2017 | PMID: 28592523 |
| Characterization of melanoma susceptibility genes in high-risk patients from Central Italy. | Pellegrini C | Melanoma research | 2017 | PMID: 28146043 |
| 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 |
| CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma. | Betti M | Cancer letters | 2016 | PMID: 27181379 |
| 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 |
| Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. | Puig S | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681309 |
| Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. | Roberts NJ | Cancer discovery | 2016 | PMID: 26658419 |
| Germline CDKN2A mutations in childhood melanoma: a case of melanoma-pancreatic cancer syndrome. | Gironi LC | International journal of dermatology | 2015 | PMID: 26381259 |
| 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 |
| CDKN2A unclassified variants in familial malignant melanoma: combining functional and computational approaches for their assessment. | Scaini MC | Human mutation | 2014 | PMID: 24659262 |
| Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family. | Maubec E | Journal of the American Academy of Dermatology | 2012 | PMID: 22841127 |
| Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma. | Nikolaou V | The British journal of dermatology | 2011 | PMID: 21801156 |
| Classifying variants of CDKN2A using computational and laboratory studies. | Miller PJ | Human mutation | 2011 | PMID: 21462282 |
| Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. | McKenzie HA | Human mutation | 2010 | PMID: 20340136 |
| Head and neck squamous cell carcinoma in FAMMM syndrome. | Vinarsky V | Head & neck | 2009 | PMID: 19360740 |
| 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 |
| Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries. | Goldstein AM | International journal of cancer | 2007 | PMID: 17397031 |
| 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 |
| Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. | Begg CB | Journal of the National Cancer Institute | 2005 | PMID: 16234564 |
| 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 |
| Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
| INK4/ARF germline alterations in pancreatic cancer patients. | Ghiorzo P | Annals of oncology : official journal of the European Society for Medical Oncology | 2004 | PMID: 14679123 |
| Geographical variation in the penetrance of CDKN2A mutations for melanoma. | Bishop DT | Journal of the National Cancer Institute | 2002 | PMID: 12072543 |
| Multiple primary melanoma revisited. | Blackwood MA | Cancer | 2002 | PMID: 12001124 |
| High prevalence of the G101W germline mutation in the CDKN2A (P16(ink4a)) gene in 62 Italian malignant melanoma families. | Mantelli M | American journal of medical genetics | 2002 | PMID: 11807902 |
| Sporadic multiple primary melanoma cases: CDKN2A germline mutations with a founder effect. | Auroy S | Genes, chromosomes & cancer | 2001 | PMID: 11579459 |
| CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation. | Della Torre G | British journal of cancer | 2001 | PMID: 11556834 |
| A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families. | Ciotti P | American journal of human genetics | 2000 | PMID: 10869234 |
| Characterization of ligurian melanoma families and risk of occurrence of other neoplasia. | Ghiorzo P | International journal of cancer | 1999 | PMID: 10508477 |
| Functional reassessment of P16 variants using a transfection-based assay. | Walker GJ | International journal of cancer | 1999 | PMID: 10389768 |
| 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 |
| Inhibition of growth of human leukemia cell lines by retrovirally expressed wild-type p16INK4A. | Gombart AF | Leukemia | 1997 | PMID: 9324288 |
| Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. | Kees UR | Blood | 1997 | PMID: 9166859 |
| Tumor suppressor p16INK4A: structural characterization of wild-type and mutant proteins by NMR and circular dichroism. | Tevelev A | Biochemistry | 1996 | PMID: 8755727 |
| Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma. | Parry D | Molecular and cellular biology | 1996 | PMID: 8668202 |
| Familial melanoma and pancreatic cancer. Ligurian Skin Tumor Study Group. | Ciotti P | The New England journal of medicine | 1996 | PMID: 8552158 |
| Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. | Sill H | Blood | 1995 | PMID: 7718873 |
| Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. | Whelan AJ | The New England journal of medicine | 1995 | PMID: 7666917 |
| Mutations associated with familial melanoma impair p16INK4 function. | Ranade K | Nature genetics | 1995 | PMID: 7647780 |
| p16 proteins from melanoma-prone families are deficient in binding to Cdk4. | Reymond A | Oncogene | 1995 | PMID: 7566978 |
| Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. | Mori T | Cancer research | 1994 | PMID: 8012957 |
| Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. | Kamb A | Nature genetics | 1994 | PMID: 7987388 |
| Germline p16 mutations in familial melanoma. | Hussussian CJ | Nature genetics | 1994 | PMID: 7987387 |
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Text-mined citations for rs104894094 ...
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Record last updated Nov 03, 2024
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