This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ClinVar Genomic variation as it relates to human health
NM_000077.5(CDKN2A):c.373G>C (p.Asp125His)
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.
(13)
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.
Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(2)
Uncertain significance(10); Likely benign(2)
13
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000077.5(CDKN2A):c.373G>C (p.Asp125His)
Variation ID: 41577 Accession: VCV000041577.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p21.3 9: 21970986 (GRCh38) [ NCBI UCSC ] 9: 21970985 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 8, 2024 Sep 15, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000077.5:c.373G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000068.1:p.Asp125His missense NM_058195.4:c.*17G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_001195132.2:c.373G>C NP_001182061.1:p.Asp125His missense NM_001363763.2:c.220G>C NP_001350692.1:p.Asp74His missense NM_058197.5:c.*296G>C 3 prime UTR NC_000009.12:g.21970986C>G NC_000009.11:g.21970985C>G NG_007485.1:g.28506G>C LRG_11:g.28506G>C LRG_11t1:c.373G>C LRG_11p1:p.Asp125His - Protein change
- D125H, D74H
- Other names
- -
- Canonical SPDI
- NC_000009.12:21970985:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00020 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00023
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00022
- 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. |
|||
| 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. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 15, 2024 | RCV000034479.17 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV000122948.13 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 25, 2021 | RCV000166832.11 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 20, 2023 | RCV000410592.5 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000855586.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely benign
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000217646.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain significance
(Mar 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695345.8
First in ClinVar: Apr 12, 2013 Last updated: Jun 29, 2024 |
Comment:
Variant summary: CDKN2A c.373G>C (p.Asp125His) 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.373G>C (p.Asp125His) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 1612370 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold 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 Non-Finnish European origin. c.373G>C has been reported in the literature in multiple isolated reports of individuals affected with cutaneous/malignant/familial melanoma, colorectal cancer, breast cancer, childhood B-ALL, and among individuals in a study of patients enrolled in the Mayo Clinic Pancreatic Cancer patient registry (example, Begg_2005, Berwick_2006, Yurgelun_2017, Tung_2015, Xu_2015). One study examining the prevalence and predictors of germline CDKN2A mutations in melanoma cases from Australia, Spain and the UK reported this variant as "non-pathogenic" (Harland_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kimura_2022, Li_2022). The following publications have been ascertained in the context of this evaluation (PMID: 21462282, 25780468, 25186627, 26483394, 16896043, 18335566, 17218939, 12072543, 16234564, 19320745, 15146471, 26104880, 28135145, 27756164, 27960642, 28765326, 9166859, 16818274, 18519632, 7718873, 29758216, 10398427, 35001868, 34369425). ClinVar contains an entry for this variant (Variation ID: 41577). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
|
Uncertain significance
(Aug 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805827.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
|
|
Uncertain significance
(Aug 25, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534334.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CDKN2A c.373G>C (p.D125H) variant has been reported in heterozygosity in individuals with melanoma, breast cancer, and colorectal cancer (PMID: 10398427, 19320745, 17218939, 16818274, 12072543, … (more)
The CDKN2A c.373G>C (p.D125H) variant has been reported in heterozygosity in individuals with melanoma, breast cancer, and colorectal cancer (PMID: 10398427, 19320745, 17218939, 16818274, 12072543, 21462282, 25186627, 25780468, 26104880, 2813514, 29758216). This variant was observed in 25/125522 chromosomes in the Non-Finnish European population, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 41577). Functional studies have not been performed and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Oct 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002012439.2
First in ClinVar: Nov 11, 2021 Last updated: Dec 24, 2022 |
Comment:
The CDKN2A c.373G>C (p.Asp125His) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-21970985-C-G). Six of six in silico tools predict a … (more)
The CDKN2A c.373G>C (p.Asp125His) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-21970985-C-G). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two families where at least two affected individuals in each family harbored the variant (PP1; PMID: 32989607), in an individual with a first-degree relative with melanoma (PS4_supporting; PMID: 12072543), as well as in three individuals with presumed sporadic melanoma (PMID: 17218939). In addition, it has been reported in one individual with pancreatic cancer (PMID: 26483394), three individuals with osteosarcoma (PMID: 32191290), two individuals with acute lymphoblastic leukemia (PMID: 26104880), and one individual with colorectal cancer (PMID: 28944238). It has also been reported in a total of three non-cancer control subjects (PMID: 27640074, 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria applied: PS4_supporting, PP1, BP4. (less)
|
|
|
Uncertain significance
(Oct 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888055.3
First in ClinVar: Sep 13, 2018 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.0002 (25/125522 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.0002 (25/125522 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in multiple individuals with melanoma as well as in unaffected controls (PMIDs: 10398427 (1999), 16234564 (2005), 19320745 (2009), 21325014 (2011), 25780468 (2014), and 29641532 (2018)). Additionally, it has been reported in affected individuals with childhood leukemia (PMID:26104880 (2015)), breast cancer (PMID: 25186627 (2015)), pancreatic cancer (PMID: 26483394 (2016)), osteosarcoma (PMID: 32191290 (2020)), and colorectal cancer (PMIDs: 28135145 (2017) and 28944238 (2017)). Published functional studies have reported inconclusive results on the effect this variant on CDK2NA protein function (PMID: 35001868 (2022), 34369425 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial melanoma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166206.12
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 125 of the CDKN2A (p16INK4a) protein (p.Asp125His). This variant is present in population databases (rs146179135, gnomAD 0.02%). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 10398427, 12072543, 17218939, 19320745, 25780468, 26483394). ClinVar contains an entry for this variant (Variation ID: 41577). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090823.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
|
|
|
Likely benign
(Aug 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902694.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
|
Uncertain significance
(Sep 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292540.15
First in ClinVar: Apr 12, 2013 Last updated: Oct 08, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10398427, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10398427, 16234564, 17218939, 16896043, 25780468, 21325014, 20707869, 21462282, 26104880, 12072543, 22703879, 23819521, 26483394, 28822769, 28135145, 15146471, 19320745, 25186627, 29641532, 18335566, 32191290, 35001868, 34369425, 28944238, 34326862) (less)
|
|
|
Uncertain significance
(Aug 24, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488760.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma-pancreatic cancer syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018558.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
|
|
variant of unknown significance
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043252.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
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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Comment:
Comment:
Variant summary: CDKN2A c.373G>C (p.Asp125His) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 1612370 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold 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 Non-Finnish European origin. c.373G>C has been reported in the literature in multiple isolated reports of individuals affected with cutaneous/malignant/familial melanoma, colorectal cancer, breast cancer, childhood B-ALL, and among individuals in a study of patients enrolled in the Mayo Clinic Pancreatic Cancer patient registry (example, Begg_2005, Berwick_2006, Yurgelun_2017, Tung_2015, Xu_2015). One study examining the prevalence and predictors of germline CDKN2A mutations in melanoma cases from Australia, Spain and the UK reported this variant as "non-pathogenic" (Harland_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kimura_2022, Li_2022). The following publications have been ascertained in the context of this evaluation (PMID: 21462282, 25780468, 25186627, 26483394, 16896043, 18335566, 17218939, 12072543, 16234564, 19320745, 15146471, 26104880, 28135145, 27756164, 27960642, 28765326, 9166859, 16818274, 18519632, 7718873, 29758216, 10398427, 35001868, 34369425). ClinVar contains an entry for this variant (Variation ID: 41577). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
The CDKN2A c.373G>C (p.Asp125His) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-21970985-C-G). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two families where at least two affected individuals in each family harbored the variant (PP1; PMID: 32989607), in an individual with a first-degree relative with melanoma (PS4_supporting; PMID: 12072543), as well as in three individuals with presumed sporadic melanoma (PMID: 17218939). In addition, it has been reported in one individual with pancreatic cancer (PMID: 26483394), three individuals with osteosarcoma (PMID: 32191290), two individuals with acute lymphoblastic leukemia (PMID: 26104880), and one individual with colorectal cancer (PMID: 28944238). It has also been reported in a total of three non-cancer control subjects (PMID: 27640074, 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria applied: PS4_supporting, PP1, BP4.
Comment:
The frequency of this variant in the general population, 0.0002 (25/125522 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in multiple individuals with melanoma as well as in unaffected controls (PMIDs: 10398427 (1999), 16234564 (2005), 19320745 (2009), 21325014 (2011), 25780468 (2014), and 29641532 (2018)). Additionally, it has been reported in affected individuals with childhood leukemia (PMID:26104880 (2015)), breast cancer (PMID: 25186627 (2015)), pancreatic cancer (PMID: 26483394 (2016)), osteosarcoma (PMID: 32191290 (2020)), and colorectal cancer (PMIDs: 28135145 (2017) and 28944238 (2017)). Published functional studies have reported inconclusive results on the effect this variant on CDK2NA protein function (PMID: 35001868 (2022), 34369425 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 125 of the CDKN2A (p16INK4a) protein (p.Asp125His). This variant is present in population databases (rs146179135, gnomAD 0.02%). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 10398427, 12072543, 17218939, 19320745, 25780468, 26483394). ClinVar contains an entry for this variant (Variation ID: 41577). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10398427, 16234564, 17218939, 16896043, 25780468, 21325014, 20707869, 21462282, 26104880, 12072543, 22703879, 23819521, 26483394, 28822769, 28135145, 15146471, 19320745, 25186627, 29641532, 18335566, 32191290, 35001868, 34369425, 28944238, 34326862)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
Converted during submission to Uncertain significance.
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:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: CDKN2A c.373G>C (p.Asp125His) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 1612370 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold 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 Non-Finnish European origin. c.373G>C has been reported in the literature in multiple isolated reports of individuals affected with cutaneous/malignant/familial melanoma, colorectal cancer, breast cancer, childhood B-ALL, and among individuals in a study of patients enrolled in the Mayo Clinic Pancreatic Cancer patient registry (example, Begg_2005, Berwick_2006, Yurgelun_2017, Tung_2015, Xu_2015). One study examining the prevalence and predictors of germline CDKN2A mutations in melanoma cases from Australia, Spain and the UK reported this variant as "non-pathogenic" (Harland_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kimura_2022, Li_2022). The following publications have been ascertained in the context of this evaluation (PMID: 21462282, 25780468, 25186627, 26483394, 16896043, 18335566, 17218939, 12072543, 16234564, 19320745, 15146471, 26104880, 28135145, 27756164, 27960642, 28765326, 9166859, 16818274, 18519632, 7718873, 29758216, 10398427, 35001868, 34369425). ClinVar contains an entry for this variant (Variation ID: 41577). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
The CDKN2A c.373G>C (p.Asp125His) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-21970985-C-G). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two families where at least two affected individuals in each family harbored the variant (PP1; PMID: 32989607), in an individual with a first-degree relative with melanoma (PS4_supporting; PMID: 12072543), as well as in three individuals with presumed sporadic melanoma (PMID: 17218939). In addition, it has been reported in one individual with pancreatic cancer (PMID: 26483394), three individuals with osteosarcoma (PMID: 32191290), two individuals with acute lymphoblastic leukemia (PMID: 26104880), and one individual with colorectal cancer (PMID: 28944238). It has also been reported in a total of three non-cancer control subjects (PMID: 27640074, 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria applied: PS4_supporting, PP1, BP4.
Comment:
The frequency of this variant in the general population, 0.0002 (25/125522 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in multiple individuals with melanoma as well as in unaffected controls (PMIDs: 10398427 (1999), 16234564 (2005), 19320745 (2009), 21325014 (2011), 25780468 (2014), and 29641532 (2018)). Additionally, it has been reported in affected individuals with childhood leukemia (PMID:26104880 (2015)), breast cancer (PMID: 25186627 (2015)), pancreatic cancer (PMID: 26483394 (2016)), osteosarcoma (PMID: 32191290 (2020)), and colorectal cancer (PMIDs: 28135145 (2017) and 28944238 (2017)). Published functional studies have reported inconclusive results on the effect this variant on CDK2NA protein function (PMID: 35001868 (2022), 34369425 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 125 of the CDKN2A (p16INK4a) protein (p.Asp125His). This variant is present in population databases (rs146179135, gnomAD 0.02%). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 10398427, 12072543, 17218939, 19320745, 25780468, 26483394). ClinVar contains an entry for this variant (Variation ID: 41577). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10398427, 16234564, 17218939, 16896043, 25780468, 21325014, 20707869, 21462282, 26104880, 12072543, 22703879, 23819521, 26483394, 28822769, 28135145, 15146471, 19320745, 25186627, 29641532, 18335566, 32191290, 35001868, 34369425, 28944238, 34326862)
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Comment:
Converted during submission to Uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance. | Kimura H | eLife | 2022 | PMID: 35001868 |
| The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia. | Li C | Pharmacogenetics and genomics | 2022 | PMID: 34369425 |
| Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma. | Mirabello L | JAMA oncology | 2020 | PMID: 32191290 |
| Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2. | Ten Broeke SW | Gastroenterology | 2018 | PMID: 29758216 |
| Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. | Pritchard AL | PloS one | 2018 | PMID: 29641532 |
| 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 |
| Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
| Biallelic loss of CDKN2A is associated with poor response to treatment in pediatric acute lymphoblastic leukemia. | Braun M | Leukemia & lymphoma | 2017 | PMID: 27756164 |
| The role of CDKN2A/B deletions in pediatric acute lymphoblastic leukemia. | Carrasco Salas P | Pediatric hematology and oncology | 2016 | PMID: 27960642 |
| Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. | Hu C | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2016 | PMID: 26483394 |
| Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. | Xu H | Nature communications | 2015 | PMID: 26104880 |
| 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 |
| 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 |
| 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 |
| Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. | Cust AE | Journal of medical genetics | 2011 | PMID: 21325014 |
| Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients. | Council ML | Experimental dermatology | 2009 | PMID: 19320745 |
| 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 use of hierarchical models for estimating relative risks of individual genetic variants: an application to a study of melanoma. | Capanu M | Statistics in medicine | 2008 | PMID: 18335566 |
| CDKN2A germline mutations in individuals with cutaneous malignant melanoma. | Orlow I | The Journal of investigative dermatology | 2007 | PMID: 17218939 |
| The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study. | Berwick M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2006 | PMID: 16896043 |
| The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. | Mirebeau D | Haematologica | 2006 | PMID: 16818274 |
| Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. | Begg CB | Journal of the National Cancer Institute | 2005 | PMID: 16234564 |
| Familial melanoma, pancreatic cancer and germline CDKN2A mutations. | Goldstein AM | Human mutation | 2004 | PMID: 15146471 |
| Geographical variation in the penetrance of CDKN2A mutations for melanoma. | Bishop DT | Journal of the National Cancer Institute | 2002 | PMID: 12072543 |
| CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. | Holland EA | Genes, chromosomes & cancer | 1999 | PMID: 10398427 |
| Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. | Kees UR | Blood | 1997 | PMID: 9166859 |
| Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. | Sill H | Blood | 1995 | PMID: 7718873 |
| Radiation doses and detriment from chest x-ray examinations. | Huda W | Physics in medicine and biology | 1989 | PMID: 2813514 |
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Text-mined citations for rs146179135 ...
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Record last updated Oct 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.