This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000075.4(CDK4):c.70C>T (p.Arg24Cys)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000075.4(CDK4):c.70C>T (p.Arg24Cys)
Variation ID: 16928 Accession: VCV000016928.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q14.1 12: 57751648 (GRCh38) [ NCBI UCSC ] 12: 58145431 (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 4, 2013 May 1, 2024 Dec 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000075.4:c.70C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000066.1:p.Arg24Cys missense NC_000012.12:g.57751648G>A NC_000012.11:g.58145431G>A NG_007484.2:g.5734C>T LRG_490:g.5734C>T LRG_490t1:c.70C>T P11802:p.Arg24Cys - Protein change
- R24C
- Other names
- -
- Canonical SPDI
- NC_000012.12:57751647:G:A
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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. |
|||
| CDK4 | No evidence available | No evidence available |
GRCh38 GRCh37 |
561 | 1069 | |
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 (2) |
criteria provided, single submitter
|
May 26, 2016 | RCV000018436.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 6, 2022 | RCV000168188.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000426326.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438126.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000420489.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 27, 2023 | RCV000584153.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2016 | RCV000484583.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568686.3
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine … (more)
This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Sep 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial melanoma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218852.8
First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 16928). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the … (more)
ClinVar contains an entry for this variant (Variation ID: 16928). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CDK4 function (PMID: 7652577, 11756559). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with melanoma (PMID: 8528263, 23384855). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs11547328, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CDK4 protein (p.Arg24Cys). (less)
|
|
|
Pathogenic
(Dec 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002664138.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at … (more)
The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature to segregate with melanoma in six different families (Zuo L et al. Nat. Genet., 1996 Jan;12:97-9; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70). Additionally, this variant has been shown to disrupt p16INK4a binding and inhibition of CDK4, which results in an increase in CDK4 kinase activity (Wölfel T et al. Science, 1995 Sep;269:1281-4). Mouse in vivo studies demonstrated that mice with this variant showed significantly increased susceptibility to the development of CDK4 related tumors (Rane SG et al. Mol. Cell. Biol., 2002 Jan;22:644-56). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial melanoma
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695325.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
Comment:
Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). … (more)
Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689576.3
First in ClinVar: Feb 19, 2018 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant impairs interaction with CDKN2A (p16-INK4a) preventing inhibition by p16-INK4a and allowing for unregulated CDK4 kinase activity, cell cycle progression and cellular transformation (PMID: 11756559, 7652577, 9228064). This variant has been reported in individuals affected with melanoma (PMID: 8528263, 22804906 23384855) and has been shown to segregate with disease (PMID: 23384855, 8528263). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488638.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
|
|
|
risk factor
(Jan 01, 1996)
|
no assertion criteria provided
Method: literature only
|
MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 3
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000038718.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 06, 2019 |
Comment on evidence:
In a cutaneous malignant melanoma-3 (CMM3; 609048) cell line, Wolfel et al. (1995) identified an arg24-to-cys (R24C) mutation in the CDK4 gene. The mutated CDK4 … (more)
In a cutaneous malignant melanoma-3 (CMM3; 609048) cell line, Wolfel et al. (1995) identified an arg24-to-cys (R24C) mutation in the CDK4 gene. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastatic tissue, but not in the patient's lymphocytes, indicating a somatic mutation. The R24C mutation was part of the CDK4 peptide recognized by cytolytic T lymphocytes and prevented binding of the CDK4 inhibitor p16(INK4A) (600160), but not of p21 (300237) or of p27 (KIP1; 600778). The results suggested that mutation of CDK4 disrupted the cell cycle regulation exerted by the tumor suppressor p16, resulting in a genetic predisposition to melanoma. The same mutation, typical of a UV lesion, was found in 1 additional melanoma among 28 melanomas analyzed. The mutated CDK4 protein had been identified as a tumor-specific antigen recognized by HLA-A 2.1 restricted autologous cytolytic T lymphocytes in the human melanoma tissue. Wolfel et al. (1995) suggested that the tumor-specific antigen defined by the R24C mutation in this patient became a target of tumor rejection responses because the patient had remained free of detectable disease for 7 years. Zuo et al. (1996) identified the R24C mutation as a germline mutation in 2 families with malignant melanoma. The mutation was detected in 11 of 11 melanoma patients, 2 of 17 unaffected individuals, and in none of 5 spouses. Although the R24C mutation has a specific effect on the CDK4 p16(INK4A)-binding domain, it has no effect on the ability of CDK4 to bind cyclin D and form a functional kinase. Zuo et al. (1996) concluded that the germline R24C mutation generates a dominant oncogene that is resistant to normal physiologic inhibition by p16(INK4A). They noted that the only previous example of a dominant oncogene transmitted in the human germline was the RET (164761) gene that gives rise to MEN2A (171400), MEN2B (162300), and medullary thyroid carcinoma (171400). (less)
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant melanoma of skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505860.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505861.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple myeloma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505862.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 16928). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CDK4 function (PMID: 7652577, 11756559). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with melanoma (PMID: 8528263, 23384855). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs11547328, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CDK4 protein (p.Arg24Cys).
Comment:
The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature to segregate with melanoma in six different families (Zuo L et al. Nat. Genet., 1996 Jan;12:97-9; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70). Additionally, this variant has been shown to disrupt p16INK4a binding and inhibition of CDK4, which results in an increase in CDK4 kinase activity (Wölfel T et al. Science, 1995 Sep;269:1281-4). Mouse in vivo studies demonstrated that mice with this variant showed significantly increased susceptibility to the development of CDK4 related tumors (Rane SG et al. Mol. Cell. Biol., 2002 Jan;22:644-56). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant impairs interaction with CDKN2A (p16-INK4a) preventing inhibition by p16-INK4a and allowing for unregulated CDK4 kinase activity, cell cycle progression and cellular transformation (PMID: 11756559, 7652577, 9228064). This variant has been reported in individuals affected with melanoma (PMID: 8528263, 22804906 23384855) and has been shown to segregate with disease (PMID: 23384855, 8528263). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified 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:
This pathogenic variant is denoted CDK4 c.70C>T at the cDNA level, p.Arg24Cys (R24C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been reported to segregate with melanoma in several melanoma families (Zuo 1996, Puntervoll 2013). Functional studies have shown that this variant disrupts binding with CDKN2A, resulting in resistance to CDKN2A inhibition and increased CDK4 kinase activity (Wolfel 1995, Rane 2002). CDK4 Arg24Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDK4 Arg24Cys occurs at a position that is conserved across species and is located in the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 16928). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CDK4 function (PMID: 7652577, 11756559). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with melanoma (PMID: 8528263, 23384855). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs11547328, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CDK4 protein (p.Arg24Cys).
Comment:
The p.R24C pathogenic mutation (also known as c.70C>T), located in coding exon 1 of the CDK4 gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature to segregate with melanoma in six different families (Zuo L et al. Nat. Genet., 1996 Jan;12:97-9; Puntervoll HE et al. J. Med. Genet., 2013 Apr;50:264-70). Additionally, this variant has been shown to disrupt p16INK4a binding and inhibition of CDK4, which results in an increase in CDK4 kinase activity (Wölfel T et al. Science, 1995 Sep;269:1281-4). Mouse in vivo studies demonstrated that mice with this variant showed significantly increased susceptibility to the development of CDK4 related tumors (Rane SG et al. Mol. Cell. Biol., 2002 Jan;22:644-56). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant summary: The CDK4 c.70C>T (p.Arg24Cys) variant involves the alteration of a conserved nucleotide and is located in protein kinase domain of the protein (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121378 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDK4 variant (0.00002). This variant has been reported in six unrelated cutaneous malignant melanoma families including evidence of cosegregation with disease (Zuo_1996, Ghiorzo_2012, Puntervoll_2013). In vivo mice-model study shows the recapitulation of melanoma phenotype (Rane_2002). The codon p.Arg24 is a mutational hot-spot in which another mutation p.Arg24His is known to be pathogenic. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This missense variant replaces arginine with cysteine at codon 24 of the CDK4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant impairs interaction with CDKN2A (p16-INK4a) preventing inhibition by p16-INK4a and allowing for unregulated CDK4 kinase activity, cell cycle progression and cellular transformation (PMID: 11756559, 7652577, 9228064). This variant has been reported in individuals affected with melanoma (PMID: 8528263, 22804906 23384855) and has been shown to segregate with disease (PMID: 23384855, 8528263). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. | Puntervoll HE | Journal of medical genetics | 2013 | PMID: 23384855 |
| MC1R variation and melanoma risk in relation to host/clinical and environmental factors in CDKN2A positive and negative melanoma patients. | Ghiorzo P | Experimental dermatology | 2012 | PMID: 22804906 |
| Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. | Rane SG | Molecular and cellular biology | 2002 | PMID: 11756559 |
| Identification of CDK4 sequences involved in cyclin D1 and p16 binding. | Coleman KG | The Journal of biological chemistry | 1997 | PMID: 9228064 |
| Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. | Zuo L | Nature genetics | 1996 | PMID: 8528263 |
| A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. | Wölfel T | Science (New York, N.Y.) | 1995 | PMID: 7652577 |
| http://docm.genome.wustl.edu/variants/ENST00000257904:c.70C>T | - | - | - | - |
Text-mined citations for rs11547328 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.