ClinVar Genomic variation as it relates to human health
NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(6); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)
Variation ID: 135825 Accession: VCV000135825.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q14.1 12: 57750663 (GRCh38) [ NCBI UCSC ] 12: 58144446 (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 Dec 6, 2016 May 1, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000075.4:c.625C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000066.1:p.Arg209Cys missense NC_000012.12:g.57750663G>A NC_000012.11:g.58144446G>A NG_007484.2:g.6719C>T LRG_490:g.6719C>T LRG_490t1:c.625C>T - Protein change
- R209C
- Other names
- p.R209C:CGT>TGT
- Canonical SPDI
- NC_000012.12:57750662:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00028
The Genome Aggregation Database (gnomAD) 0.00029
The Genome Aggregation Database (gnomAD), exomes 0.00035
Exome Aggregation Consortium (ExAC) 0.00037
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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CDK4 | No evidence available | No evidence available |
GRCh38 GRCh37 |
550 | 1049 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 17, 2021 | RCV000130933.17 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 6, 2024 | RCV000235157.23 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Aug 30, 2023 | RCV000409800.14 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Oct 27, 2023 | RCV000586938.25 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV001086259.15 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Feb 17, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534257.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Jul 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488928.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010276.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Uncertain significance
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004020048.1
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.
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Likely benign
(Jun 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695320.4
First in ClinVar: Mar 17, 2018 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CDK4 c.625C>T (p.Arg209Cys) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three … (more)
Variant summary: CDK4 c.625C>T (p.Arg209Cys) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three 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 251492 control chromosomes, predominantly within Northwestern European (at a frequency of 0.0008) and Swedish European subpopulations (at a frequency of 0.0008) in the gnomAD database (v2.1). These observed subpopulation frequencies are approximately 40 fold higher than the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (i.e. 8e-04 vs. 2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in European subpopulations. The variant, c.625C>T, has been reported in the literature in an individual affected with melanoma (e.g., Borroni 2017), and other individuals affected with pancreatic (e.g., Chaffee 2018) breast cancer (e.g., Li 2016, Tung 2015, Schubert_2019), and co-occurring breast and thyroid cancer (e.g., Bakos_2021), although with limited information (i.e. lack of co-occurrence and cosegregation data); moreover, four of these breast cancer cases were of western/northern European ancestry. These reports therefore do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28060055, 28726808, 26534844, 27640074, 26252490, 25186627, 26580448, 34130653, 30426508). Ten ClinVar submitters (evaluation after 2014) have cited the variant and classified it as VUS (n=6) and likely benign (n=4). At-least one additional submitter has re-classified this variant from a VUS to likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Melanoma, cutaneous malignant, susceptibility to, 3
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000891027.4
First in ClinVar: Mar 19, 2019 Last updated: Sep 01, 2023 |
Comment:
The CDK4 c.625C>T (p.Arg209Cys) missense change has a maximum subpopulation frequency of 0.065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The CDK4 c.625C>T (p.Arg209Cys) missense change has a maximum subpopulation frequency of 0.065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with pancreatic cancer (PMID: 28726808) and breast cancer (PMID: 25186627, 26534844). To our knowledge, this variant has not been reported in individuals with familial melanoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Oct 27, 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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GeneDx
Accession: SCV000210930.17
First in ClinVar: Feb 24, 2015 Last updated: Nov 25, 2023 |
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: 26252490, … (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: 26252490, 26534844, 28060055, 25801821, 28380455, 26580448, 28726808, 25186627, 27640074, 30374176, 33281875) (less)
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Likely benign
(May 12, 2023)
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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: SCV000601007.4
First in ClinVar: Dec 06, 2016 Last updated: Jan 06, 2024 |
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Uncertain significance
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550003.5
First in ClinVar: Jul 30, 2022 Last updated: Feb 14, 2024 |
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Likely benign
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial melanoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166201.15
First in ClinVar: Jun 16, 2014 Last updated: Feb 28, 2024 |
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Likely benign
(Jun 15, 2018)
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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: SCV000185845.8
First in ClinVar: Aug 06, 2014 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)
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Uncertain significance
(Mar 02, 2018)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000787990.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971655.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798568.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Co-occurrence of thyroid and breast cancer is associated with an increased oncogenic SNP burden. | Bakos B | BMC cancer | 2021 | PMID: 34130653 |
The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. | Schubert S | International journal of cancer | 2019 | PMID: 30426508 |
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. | Chaffee KG | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28726808 |
Targeted next generation sequencing of mucosal melanomas identifies frequent NF1 and RAS mutations. | Cosgarea I | Oncotarget | 2017 | PMID: 28380455 |
Genetic counselling and high-penetrance susceptibility gene analysis reveal the novel CDKN2A p.D84V (c.251A>T) mutation in melanoma-prone families from Italy. | Borroni RG | Melanoma research | 2017 | PMID: 28060055 |
Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease. | Lubbe SJ | Neurobiology of aging | 2016 | PMID: 27640074 |
Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families. | Li J | Journal of medical genetics | 2016 | PMID: 26534844 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies. | N N | PloS one | 2015 | PMID: 26252490 |
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 |
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Text-mined citations for rs140644696 ...
HelpRecord last updated May 01, 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.